Altered mGluR1/5-driven plasticity in the motor cortical surface as a biomarker for Parkinson’s disease

Altered mGluR1/5-driven plasticity in the motor cortical surface as a biomarker for Parkinson’s disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Altered mGluR 1/5 -driven plasticity in the motor cortical surface as a biomarker for Parkinson’s disease Hongseong Shin, Taewoo Ko, Yoon Ji Kwon, Hyunjung Hwang, Yang Tae Kim, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7634193/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Parkinson’s disease (PD), a neurodegenerative disorder, is caused by dopaminergic lesions in the substantia nigra pars compacta that lead to motor deficits. Although metabotropic glutamate receptors (mGluRs) are key regulators of synaptic plasticity, their contribution to cortical surface long-term depression (LTD) in PD remains unknown. We used the 6-hydroxydopamine (6-OHDA) rat model of PD to examine synaptic plasticity in the primary motor cortex (M1) surface. Extracellular field recordings revealed that mGluR-dependent LTD induced by paired-pulse low-frequency stimulation (pp-LFS) was markedly reduced in PD rats, whereas N-methyl-D-aspartate receptor (NMDAR)-dependent LTD remained unchanged. Whole-cell patch-clamp recordings showed altered action potential (AP) kinetics, such as narrower spike half-widths and faster repolarization, in PD neurons on the M1 surface, suggesting that reduced LTD and sharper AP kinetics contribute to motor deficits. Combined with previous evidence of enhanced mGluR 1/5 -dependent long-term potentiation (LTP) in PD, these results indicate the involvement of a selective disruption of mGluR-mediated plasticity in maladaptive plasticity and motor dysfunction. Our study highlights group I mGluRs as both key modulators of sensorimotor homeostasis and potential therapeutic targets for restoring the synaptic balance following alteration by sensorimotor deficits. Health sciences/Neurology Biological sciences/Neuroscience Parkinson’s disease Sensorimotor cortex Motor cortex Long-term synaptic plasticity Metabotropic glutamate receptor Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons, primarily in the substantia nigra pars compacta (SNc), which leads to profound disruptions in motor function 1 – 4 . A major consequence of this nigral degeneration is a weakening of motor command and control both to and from the primary motor cortex (M1). As the M1 is crucial for executing precise motor commands, disruptions in this area contribute directly to the motor deficits observed in PD 5–8 . In particular, the surface layers of sensorimotor cortices are thought to determine cortical map organization, influence associative information processing, and play a crucial role in learning 9 – 16 . Although the motor cortex surface is relatively less understood, identifying pathological signatures in this region may provide novel targets for therapeutic interventions against PD. Reports have consistently described altered synaptic plasticity of the M1 in PD 6,7,17 . Both long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity are impaired in patients with PD 18 . Metabotropic glutamate receptors (mGluRs) are key modulators of synaptic plasticity in sensorimotor cortices, and their dysfunction is increasingly recognized as a factor contributing to PD-related motor impairments 19 , 20 . Group I mGluRs, namely mGluR 1 and mGluR 5 , not only counteract dopaminergic signaling in the healthy basal ganglia but also may influence the progression of dopaminergic degeneration in PD models 21 . Furthermore, selective blockade of mGluR 5 in the M1 reduced spontaneous locomotion and motor coordination 22 . These findings strongly suggest a crucial role of mGluRs in motor function, given that group I mGluRs are expressed in most neurons across various animal species 24 – 29 . Previously, we demonstrated the enhancement of mGluR 1/5 -driven LTP at the M1 surface in a PD model 29 and provided transcriptomic evidence showing that genes associated with synaptic plasticity are significantly altered in the M1 under PD conditions 30 . However, it remains unknown whether mGluR-mediated LTD also plays a role in PD. In this study, we aimed to investigate mGluR-driven synaptic depression within the M1 of a 6-hydroxydopamine (6-OHDA)-induced PD rat model, with a specific focus on the role of mGluRs. Our findings demonstrate the strong involvement of dysregulated mGluR activity with abnormal motor behavior in PD, thereby highlighting the critical role of mGluRs in PD pathology. Results Behavioral validation of the hemi-parkinsonian model The PD model was generated via the unilateral administration of 6-OHDA to rats. Two weeks later, the rats were subjected to apomorphine-induced rotation and rotarod tests for behavioral confirmation of PD symptoms (Fig. 1 a). In the apomorphine-induced rotation test, PD rats showed a significant increase in rotating behavior compared with control (Ctrl) rats, which exhibited minimal rotational behavior (Ctrl: 1.50 ± 4.36, n = 6 vs. PD: 121.00 ± 18.27, n = 9; t (8.890) = -6.354, P < 0.001, independent sample t -test) ( Fig. 1 b). The rotarod test also revealed significant motor impairments in the PD rats. After normalizing the data to the pre-test level, the latency to fall off the rotarod was decreased in the PD group but increased in the Ctrl group (Ctrl: 150.10% ± 18.94%, n = 4 vs. PD: 72.68% ± 10.10%, n = 5; t (7) = 3.722, P = 0.004, independent sample t -test; Fig. 1 c). These behavioral observations demonstrate the successful establishment of the PD model. To additionally confirm the loss of dopaminergic neurons after 6-OHDA administration, tyrosine hydroxylase (TH) immunostaining was performed 1 week after completion of the behavioral tests. In PD rats, the TH-positive area in the 6-OHDA-injected hemisphere (normalized to the untreated hemisphere) decreased significantly in both the SNc and Striatum (STR) (SNc-Ctrl: 96.58% ± 4.03%, n = 5 vs. SNc-PD: 13.02% ± 5.60%, n = 5; t (8) = 12.107, P < 0.001, independent sample t -test; STR-Ctrl: 101.64% ± 2.05%, n = 5 vs. STR-PD: 0.53% ± 0.13%, n = 5; t (4.031) = 49.344, P < 0.001, independent sample t -test; Fig. 1 d). These results confirm that dopamine lesions caused the motor defects in this PD rat model. Next, we verified the presence of glutamatergic synapses in the M1 surface. Extracellular field recording was performed 3 weeks after 6-OHDA injection. Stimulation and recording electrodes were placed on the M1 layer 1/2. Synaptic responses were reduced by the bath application of 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX, 10 µM), an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist. Subsequent application of tetrodotoxin (TTX, 1 µM) nearly abolished the synaptic response, confirming that glutamatergic synapses exist in the cortical surface of M1 (PD: 100.00% ± 0.00%, n = 5 vs. NBQX: 38.39% ± 8.45%, n = 5 vs. NBQX + TTX: 11.55% ± 1.87%, n = 5; F (2, 12) = 82.455, P < 0.001, one-way ANOVA with Bonferroni’s post hoc test; Fig. 1 e). These findings are consistent with those of our previous study 29 . Selective impairment of mGluR-dependent LTD in PD To investigate the contribution of mGluRs to LTD in the M1 surface, we applied two previously well-established protocols for inducing LTD in cortical slices: (i) mGluR-dependent LTD (or mGluR-LTD) induced by paired-pulse low-frequency stimulation (pp-LFS; 900 pairs of pulses delivered at 1 Hz with 50-ms inter-pulse intervals), and (ii) N-methyl-D-aspartate receptor (NMDAR)-dependent LTD (i.e., NMDAR-LTD) induced by single-pulse low-frequency stimulation (sp-LFS; 900 single pulses at 1 Hz) 31 – 35 . We first verified that pp-LFS activated mGluRs but not NMDARs. Bath application of (2R)-amino-5-phosphonovaleric acid (AP5, 100 µM), an NMDAR antagonist, had little effect on pp-LFS-induced LTD in the Ctrl M1 (Ctrl: 75.70% ± 8.084%, n = 8 vs. Ctrl AP5: 80.26% ± 10.01%, n = 11, t (17) = -1.060, P = 0.152, independent sample t -test; Fig. 2 a). The additional administration of 2-methyl-6-phenylethynyl-pyridine (MPEP, 10 µM) an mGluR 5 antagonist, and (S)-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acid (LY 367385; LY, 100 µM), an mGluR 1 antagonist, completely eliminated LTD at 60 minutes post-induction, further confirming that pp-LFS-induced LTD in the M1 surface is driven by group I mGluRs under naive conditions (Ctrl: 75.70% ± 8.084%, n = 8 vs. Ctrl AP5: 80.26% ± 10.01%, n = 11 vs. Ctrl AP5 + MPEP + LY: 102.5% ± 20.74%, n = 9; F (2, 25) = 9.305, P < 0.001, one-way ANOVA). We next investigated whether PD affected mGluR-LTD in the M1, applying AP5 to prevent NMDAR activation. The finding that AP5 alone eliminated LTD (PD: 87.60% ± 10.56%, n = 10 vs. PD AP5: 100.2% ± 20.34%, n = 6; t (18) = -1.741, P = 0.049, independent sample t -test) revealed the absence of mGluR-LTD in the PD M1 surface. To further examine if PD also affected NMDAR-LTD, we applied sp-LFS, which induced LTD at the M1 surface in both Ctrl and PD slices; AP5 completely blocked LTD in both slices (Ctrl: 83.12% ± 15.17%, n = 19 vs. Ctrl AP5: 103.8% ± 18.55%, n = 8; t (25) = -3.030, P = 0.003, independent sample t -test; Fig. 2 b; PD: 82.69% ± 12.09%, n = 18 vs. PD AP5: 105.3% ± 10.76%, n = 6; t (22) = -4.068, P < 0.001, independent sample t -test). No significant difference in NMDAR-LTD amplitude was observed between the Ctrl and PD slices (Ctrl: 83.12% ± 15.17%, n = 19, PD: 82.69% ± 12.09%, n = 18; t (35) = 0.095, P = 0.463, independent sample t -test). Thus, PD does not appear to affect NMDAR-driven LTD; it is associated with changes in mGluR 1/5 -LTD, but not NMDAR-LTD, at the M1 surface. Preserved intrinsic properties with altered action potential (AP) kinetics in PD neurons To determine whether PD pathology affects the intrinsic membrane properties of M1 pyramidal neurons, we conducted whole-cell patch-clamp recordings of layer 2 neurons. Representative traces (Fig. 3 a) illustrate that Ctrl and PD neurons exhibited similar firing patterns in response to step current injections. The resting membrane potential (RMP), measured 3 minutes after break-in, did not differ significantly between the groups (Ctrl: -80.82 ± 0.39, n = 11 vs. PD: -79.80 ± 0.94, n = 8; t (9.391) = -1.004, P = 0.170, independent sample t -test; Fig. 3 b). The input resistance (R in ), assessed at -100 pA hyperpolarizing current injection, also did not differ significantly between the groups (Ctrl: 60.86 ± 5.17, n = 11 vs. PD: 59.46 ± 3.37, n = 10; t (19) = 0.221, P = 0.414, independent sample t -test; Fig. 3 c). Neuronal excitability was quantified as the number of APs generated in response to depolarizing current steps (0 to + 800 pA, 100-pA increments). Both Ctrl and PD neurons displayed a graded increase in the firing frequency, but there was no detectable difference between the groups ( F (17, 1) = 0.047, P = 1.000, two-way ANOVA; Fig. 3 d, Table 1 ). Table 1 Number of action potentials arising in layer 2/3 pyramidal neurons in response to increasing current injections. Related to Fig. 3 d. Ctrl, Control; PD, Parkinson’s disease. Current injection (pA) Group ( n ) 0 100 200 300 400 500 600 700 800 Ctrl (10) 0.00 ± 0.00 0.00 ± 0.00 0.00 ± 0.00 3.5 ± 0.31 7.25 ± 0.58 10.75 ± 0.81 14.38 ± 1.02 17.88 ± 1.02 21.00 ± 0.13 PD (10) 0.00 ± 0.00 0.00 ± 0.00 0.30 ± 0.10 2.20 ± 0.29 6.70 ± 0.42 10.50 ± 0.48 14.50 ± 0.51 17.70 ± 0.53 20.72 ± 0.37 We additionally analyzed various parameters of the AP waveform (Fig. 3 e). Representative traces of APs and their first derivatives (dV/dt) are shown for Ctrl and PD neurons. The threshold voltage (Ctrl threshold : -31.90 ± 1.11, n = 9 vs. PD threshold : -33.29 ± 1.16, n = 9; t (16) = 0.864, P = 0.200, independent sample t -test) and AP amplitude (Ctrl amplitude : 78.81 ± 1.52, n = 9 vs. PD amplitude : 77.23 ± 2.20, n = 9; t (16) = 0.651, P = 0.282, independent sample t -test) did not significantly differ between the groups. However, the AP half-width was significantly lower in PD neurons than in Ctrl neurons, indicating sharper spikes (Ctrl half−width : 1.53 ± 0.06, n = 9 vs. PD half−width : 1.37 ± 0.02, n = 9; t (10.816) = 2.774, P = 0.009, independent sample t -test). Although the maximum rise rate was unaffected (Ctrl maximum rise rate : 177.10 ± 4.32, n = 9 vs. PD maximum rise rate : 168.56 ± 7.02, n = 9; t (16) = 1.036, P = 0.158, independent sample t -test), the maximum decay rate was faster in PD (vs. Ctrl) neurons (Ctrl maximum decay rate : -46.22 ± 2.39, n = 9 vs. PD maximum decay rate : -53.37 ± 1.70, n = 9; t (16) = 2.436, P = 0.013, independent sample t -test), consistent with accelerated repolarization. The amplitude of afterhyperpolarization (AHP) did not significantly differ between the groups (Ctrl AHP : 12.81 ± 0.65, n = 9 vs. PD AHP : 14.71 ± 1.34, n = 9; t (11.582) = -1.279, P = 0.113, independent sample t -test). Finally, we quantified the spontaneous excitatory synaptic inputs by recording spontaneous excitatory postsynaptic currents (sEPSCs) at a holding potential of -70 mV. Representative traces and group analyses revealed no significant alterations in either the sEPSC amplitude (Ctrl Amplitude : 28.48, n = 11; PD Amplitude : 28.71 ± 1.50, n = 7; t (16) = -0.026, P = 0.490, independent sample t -test) or frequency (Ctrl Frequency : 2.78 ± 0.50, n = 11; PD Frequency : 3.27 ± 0.63, n = 7; t (16) = -0.599, P = 0.279, independent sample t -test) in PD neurons relative to Ctrl neurons (Fig. 3 f). Altogether, these results indicate that the intrinsic electrophysiological properties and excitatory synaptic transmission of layer 2 M1 pyramidal neurons are not significantly altered in our PD rat model. The impaired cortical plasticity observed in PD is therefore unlikely to arise from changes in neuronal excitability or excitatory inputs under unstimulated conditions. Nonetheless, the sharper AP kinetics in PD may contribute to abnormal motor function and neuroplasticity when stimulated. Discussion In this study, we investigated the dynamics of synaptic LTD in the superficial layers of the M1 of 6-OHDA PD model rats, using extracellular field recording and whole-cell patch-clamp recording. Field recording data revealed that PD is associated with a pronounced shift in mGluR 1/5 -driven synaptic plasticity, characterized by enhanced mGluR-dependent LTP and reduced mGluR-LTD. Patch-clamp data further demonstrated that the intrinsic neuronal properties and spontaneous EPSCs were largely preserved in the M1 layer 2/3 neurons of PD model animals. However, we observed significantly altered AP kinetics in PD neurons, such as narrower spike half-widths and accelerated repolarization, which indicate sharper firing activity accompanied by an increase in synaptic weight. Together with our previous report 36 , these results indicate that dopaminergic degeneration leads to an overall shift in mGluR 1/5 -driven synaptic plasticity toward increased synaptic weight at the M1 surface 29 (Fig. 4 ). This shift may reflect sensorimotor homeostasis that stabilizes cortical function and motor learning in response to denervation of the M1 from basal ganglia inputs 37 . Our findings also reveal that NMDAR-dependent mechanisms in the superficial M1 layer did not change significantly under PD conditions. This result highlights the importance of mGluR signaling in PD, consistent with several reports of interactions between dopamine and mGluR-LTD in the basal ganglia motor circuit 38 . Partial depletion of dopaminergic neurons is associated with reduced mGluR 1/5 -dependent plasticity in the indirect pathway 31 , 38 – 40 , and our data extend the body of evidence by showing that the shifts in mGluR-LTD and mGluR-LTP in the M1 surface are closely associated with dyskinesia. Abnormal mGluR-dependent plasticity is not unique to PD. mGluR dysfunction has been implicated in other neurodegenerative and neuropsychiatric disorders, including Huntington’s disease, Alzheimer’s disease, epilepsy, and depression 41 – 47 (Table 2 ). These convergent findings emphasize the broader significance of mGluRs in circuit regulation and disease progression. Nonetheless, our findings do not conclusively prove a cause-and-effect relationship between sensorimotor deficits and altered synaptic plasticity and AP kinetics. Table 2 Changes in metabotropic glutamate receptor (mGluR)-mediated long-term synaptic plasticity are associated with various neurodegenerative and neurological diseases. mGluR-driven long-term potentiation (LTP) or long-term depression (LTD) can be induced in various regions of the brain (induction methods shown in brackets) and are suppressed or enhanced under disease conditions. ↓ indicates suppression, ↑ indicates enhancement of mGluR-LTP or mGluR-LTD in disease models. HFS, high frequency stimulation; KO, knockout; LFS, low-frequency stimulation; MPEP, 2-methyl-6-phenylethynyl-pyridine; pp, paired-pulse; TBS, theta burst stimulation; DHPG, 3,5-Dihydroxyphenylglycine; ACC, anterior cingulate cortex. Disease Animal Recording site Synaptic modulation LTP LTD Parkinson’s disease 29 (This work) Sprague-Dawley rat Motor cortex superficial layer ↑ (HFS) ↓ (pp-LFS / LFS) Hearing loss/tinnitus 10 C57BL/6 mouse Auditory cortex superficial layer ↓ or ↑ (Decreased pp-LFS-LTP/ increased TBS-LTP) - Huntington’s disease 48 Wistar rat Corticostriatal fibers ↑ (3-NP) - Alzheimer’s disease 49 – 52 C57BL/6 mouse Hippocampus CA3-CA1 ↓ (HFS) ↑ or ↓ (DHPG / LFS) Depression 53 – 55 C57BL/6 mouse Hippocampus CA3-CA1 - ↑ (pp-LFS / DHPG) Epilepsy / seizures 56–58 Wistar rat Hippocampus CA3-CA1 ↑ (TBS) ↓ (pp-LFS) Fragile X syndrome 59 – 63 Fmr1 KO mouse Hippocampus CA3-CA1 Affects LTP priming (DHPG + 100 Hz HFS) ↑ (pp-LFS / DHPG) Chronic pain 64 C57BL/6 mouse ACC layer V-II/III, V-V/VI - ↓ (DHPG + MPEP/LFS) Overall, our study highlights the significant contribution of group I mGluRs to the homeostatic regulation of synaptic plasticity in the M1 superficial layer. Abnormal mGluR 1/5 -LTP and LTD in this region are closely associated with sensorimotor deficits in PD and thus may represent promising targets for therapeutic intervention. Future research should focus on identifying the neuronal populations that mediate mGluR 1/5 -driven cortical surface plasticity, mapping the specific circuits involved, and clarifying underlying cellular mechanisms such as postsynaptic AMPAR trafficking, intracellular calcium signaling, local mRNA translation, and presynaptic neurotransmitter release. Methods Animals Six-week-old male Sprague-Dawley rats were housed under a 12-hour light/dark cycle in a temperature-controlled facility (25°C) and allowed access to food and water ad libitum . All animal procedures were approved by the Institutional Animal Care and Use Committee at Incheon National University (Approval Code: INU-ANIM-2024-14) and carried out in accordance with relevant regulations. This study also adhered to ARRIVE guidelines. 6-OHDA-induced hemi-parkinsonian rat model To generate the hemi-parkinsonian PD rat model, dopaminergic neuron degeneration was induced through the stereotaxic administration of 6-OHDA (dissolved in normal saline with 0.02% ascorbic acid) into the medial forebrain bundle. The animals were anesthetized by isoflurane inhalation (2%), and a burr hole was created in one hemisphere at -3.84 mm anterior and − 1.4 mm lateral to the bregma. 6-OHDA was injected at a depth of 8.5 mm below the dura mater and an infusion rate of 0.5 µL/minute for 8 minutes using a Hamilton syringe equipped with a micropump injector (26G needle). The 6-OHDA-administered hemisphere (PD) was compared with the contralateral hemisphere (Ctrl). Apomorphine-induced rotation test To screen for 6-OHDA-induced dopamine depletion, rats were administered apomorphine (0.5 mg/kg in 0.1% ascorbic acid, subcutaneous) and placed individually in a 30-cm-diameter cylinder. Rotating behavior was recorded using a digital video camera. The number of rotations during a 30-minute observation period was manually counted. The net number of rotations was calculated as the number of contralateral rotations (away from the lesioned side) minus the number of ipsilateral rotations. Animals exhibiting at least three net contralateral rotations per minute were considered to display PD symptoms. Rotarod test The animals were trained to walk on a rotarod apparatus (Ugo Basile, Italy) prior to testing. Fourteen days after 6-OHDA administration, rats were subjected to the rotarod test at a rotation speed of 10 rpm for at least 180 seconds. The speed was gradually increased at a rate of 1 rpm every 6 seconds, and the latency to fall from the rod was recorded in two trials per rat. Data are presented as the ratio of the latency to fall after 6-OHDA administration to that before 6-OHDA administration (%). Immunohistochemistry Rats were deeply anesthetized via isoflurane inhalation (2%) and perfused transcardially with phosphate-buffered saline (PBS) and 4% paraformaldehyde (PFA). The brains were dissected and submerged in 4% PFA for 24 hours at 4°C, then submerged in 30% sucrose. Then, the brains were cut into 50-µm-thick coronal frozen sections using a cryostat (CM1520, Leica Biosystems, Germany). For TH staining, free-floating sections were washed with 0.3% Triton X-100 in PBS for 30 minutes, then incubated overnight with a rabbit anti-TH antibody (1:1,000 dilution, AB152, RRID: AB_390204, Millipore, USA). After washing with PBS, the sections were incubated with a biotinylated secondary anti-rabbit antibody (1:200 dilution, MP-7401, RRID: AB_2336529, Vector Labs, USA) for 1 hour. Antibody labeling was visualized via incubation with 3,3-diaminobenzidine for 3–5 minutes, and the sections were mounted on aminosilane-coated slides. The area of TH-positive staining in the ipsilateral hemisphere was normalized to that of the contralateral hemisphere (100%). Brain slice preparation Primary motor cortical slices were collected from hemi-parkinsonism rats. The animals were deeply anesthetized with 2% isoflurane, and the brains were rapidly removed into chilled, oxygenated dissection buffer. For extracellular field recording, slices were prepared in a sucrose-based slicing buffer containing 75.0 mM sucrose, 25.0 mM glucose, 87.0 mM NaCl, 2.5 mM KCl, 1.3 mM NaH 2 PO 4 , 25.0 mM NaHCO 3 , 7.0 mM MgCl 2 , and 0.5 mM CaCl 2 . For whole-cell patch-clamp recording, slices were prepared in a choline-based slicing buffer containing 20.0 mM glucose, 110.0 mM choline chloride, 2.5 mM KCl, 1.2 mM NaH 2 PO 4 , 7.0 mM MgCl 2 , and 0.5 mM CaCl 2 . Coronal motor cortical slices were cut using a Leica VT1200S vibratome at a 400-µm thickness for field recordings and 300-µm thickness for patch-clamp recordings. After cutting, the slices were transferred to artificial cerebrospinal fluid (ACSF; 25.0 mM glucose, 125.0 mM NaCl, 2.5 mM KCl, 1.3 mM NaH 2 PO 4 , 25.0 mM NaHCO 3 , 1.0 mM MgCl 2 , and 2.0 mM CaCl 2 for field recordings; 20.0 mM glucose, 124.0 mM NaCl, 2.5 mM KCl, 1.0 mM NaH 2 PO 4 , 26.2 mM NaHCO 3 , 1.3 mM MgCl 2 , and 2.5 mM CaCl 2 for patch recordings), which was continuously bubbled with 95% O 2 /5% CO 2 . All slices were incubated at 32°C for 12 minutes and allowed to recover for 1 h at room temperature, then transferred to a submersion-type recording chamber perfused with oxygenated ACSF at 31–32°C. Extracellular field recording Field excitatory postsynaptic potential (fEPSPs) were recorded in the primary motor cortex layer 1/2 using glass electrodes filled with ACSF. Synaptic responses were elicited by applying single electric stimulation to layer ½ through a stimulating electrode (concentric bipolar microelectrode, FHC, USA), and field potentials were recorded in the same layer. The signals were amplified (MultiClamp 700B) and digitized (Digidata 1550B, Molecular Devices). After 20 minutes of stable baseline recording, pp-LFS and sp-LFS protocols were applied. The fEPSP amplitudes were normalized to baseline, monitored for 1 h, and averaged over the last 5 minutes. Patch-clamp recording Whole-cell recordings of superficial layer (L2/3) pyramidal neurons in the motor cortex were performed. Patch pipettes (3–7 MΩ) were filled with an internal solution containing 135 mM K-gluconate, 7 mM NaCl, 10 mM HEPES, 0.2 mM EGTA, 4 mM Na 2 -ATP, and 0.2 mM Na-GTP (pH 7.3–7.4 adjusted with KOH; 292–293 mOsm adjusted with sucrose). RMP was measured 3 minutes after break-in. Intrinsic excitability was assessed in current-clamp mode by biasing the membrane potential to -70 mV via steady current injection and delivering step currents from − 400 to + 800 pA in 100-pA increments. R in was determined from the voltage responses to a -100 pA current injection. The AP properties were quantified using the first spike elicited by the minimal suprathreshold-depolarizing current injection. The AP threshold was defined as the membrane potential at which the first derivative of voltage over time (dV/dt) exceeded 20 mV/ms. The AP amplitude was calculated as the voltage difference between the AP threshold and peak AP. The AP half-width was calculated as 50% of the amplitude, which was defined as the duration between the rising and falling phases at half-maximal height. The maximum rise and decay rates were determined from the peak positive and negative dV/dt values, respectively. The AHP amplitude was measured as the difference between the threshold voltage and the most negative membrane potential reached after the AP. sEPSCs were recorded in voltage-clamp mode at a -70 mV holding potential for 3 minutes. The data were acquired with a MultiClamp 700B amplifier, digitized using a Digidata 1550B, and analyzed offline using pCLAMP software (Molecular Devices). Statistics All statistical analyses were performed using SPSS 28.0 (IBM Corp., Armonk, NY, USA). All graphs were generated using GraphPad Prism 8 (GraphPad Software Inc., La Jolla, CA, USA), and final the arrangements and labeling were completed using Adobe Illustrator CC 2019 (Adobe Inc., San Jose, CA, USA). Axon pCLAMP11 Electrophysiology Data Acquisition and Analysis Software (Molecular Devices, San Jose, CA) was used to numerically present the extracellular field recording data. Data are presented as means ± standard errors of the mean (SEMs) and it is mentioned if normalized for comparison. Declarations Author contributions S.C.Y and S.G.Y. conceptualized and designed the study; H.S, T.K, H.H and Y.T.K performed animal behavioral tests and electrophysiology recordings; H.S and Y.J.K performed data analysis; H.S, Y.J.K, J.G.K, Q.Z, S.C.Y and S.G.Y, wrote the paper; Y.J.K, Y.M.H, J.G.K, Q.Z, S.G.Y, and S.C.Y. revised the paper; S.G.Y. and S.C.Y acquired funding. Data availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare no competing financial interests. Funding This work was supported by the Innovation and Technology Commission funding of Hong Kong (PRP/050/23FX) for Sungchil Yang and by Incheon National University (International Cooperative) for Sunggu Yang. Data Availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. References Pietracupa, S. et al. Understanding the role of cerebellum in early Parkinson's disease: a structural and functional MRI study. NPJ Parkinsons Dis. 10 10.1038/s41531-024-00727-w (2024). Cagle, J. N. et al. Chronic intracranial recordings in the globus pallidus reveal circadian rhythms in Parkinson's disease. Nat. Commun. 15 , 4602. 10.1038/s41467-024-48732-0 (2024). Tansey, M. G. et al. Inflammation and immune dysfunction in Parkinson disease. Nat. Rev. Immunol. 22 , 657–673. 10.1038/s41577-022-00684-6 (2022). McGregor, M. M. & Nelson, A. B. Circuit mechanisms of Parkinson's disease. Neuron 101 , 1042–1056. 10.1016/j.neuron.2019.03.004 (2019). Rahimpour, S., Rajkumar, S. & Hallett, M. The Supplementary Motor Complex in Parkinson's Disease. J. Mov. Disord . 15 , 21–32. 10.14802/jmd.21075 (2022). Rodriguez-Sabate, C., Rodriguez, M. & Morales, I. Studying the functional connectivity of the primary motor cortex with the binarized cross recurrence plot: The influence of Parkinson's disease. PLoS One . 16 , e0252565. 10.1371/journal.pone.0252565 (2021). Guo, L. et al. Dynamic rewiring of neural circuits in the motor cortex in mouse models of Parkinson's disease. Nat. Neurosci. 18 , 1299–1309. 10.1038/nn.4082 (2015). Duty, S. Therapeutic potential of targeting group III metabotropic glutamate receptors in the treatment of Parkinson's disease. Br. J. Pharmacol. 161 , 271–287. 10.1111/j.1476-5381.2010.00882.x (2010). Huang, S., Wu, S. J., Sansone, G., Ibrahim, L. A. & Fishell, G. Layer 1 neocortex: Gating and integrating multidimensional signals. Neuron 112 , 184–200. 10.1016/j.neuron.2023.09.041 (2024). Pak, S. et al. Cortical surface plasticity promotes map remodeling and alleviates tinnitus in adult mice. Prog Neurobiol. 231 , 102543. 10.1016/j.pneurobio.2023.102543 (2023). Schuman, B., Dellal, S., Pronneke, A., Machold, R. & Rudy, B. Neocortical Layer 1: An Elegant Solution to Top-Down and Bottom-Up Integration. Annu. Rev. Neurosci. 44 , 221–252. 10.1146/annurev-neuro-100520-012117 (2021). Abs, E. et al. Learning-Related Plasticity in Dendrite-Targeting Layer 1 Interneurons. Neuron 100, 684–699 e686, (2018). 10.1016/j.neuron.2018.09.001 Ibrahim, L. A. et al. Cross-Modality Sharpening of Visual Cortical Processing through Layer-1-Mediated Inhibition and Disinhibition. Neuron 89 , 1031–1045. 10.1016/j.neuron.2016.01.027 (2016). Letzkus, J. J. et al. A disinhibitory microcircuit for associative fear learning in the auditory cortex. Nature 480 , 331–335. 10.1038/nature10674 (2011). Hosp, J. A., Molina-Luna, K., Hertler, B., Atiemo, C. O. & Luft, A. R. Dopaminergic modulation of motor maps in rat motor cortex: an in vivo study. Neuroscience 159 , 692–700. 10.1016/j.neuroscience.2008.12.056 (2009). Jacobs, K. M. & Donoghue, J. P. Reshaping the cortical motor map by unmasking latent intracortical connections. Science 251 , 944–947. 10.1126/science.2000496 (1991). Ueki, Y. et al. Altered plasticity of the human motor cortex in Parkinson's disease. Ann. Neurol. 59 , 60–71. 10.1002/ana.20692 (2006). Kishore, A., Joseph, T., Velayudhan, B., Popa, T. & Meunier, S. Early, severe and bilateral loss of LTP and LTD-like plasticity in motor cortex (M1) in de novo Parkinson's disease. Clin. Neurophysiol. 123 , 822–828. 10.1016/j.clinph.2011.06.034 (2012). Kwan, C. et al. Metabotropic glutamate receptors in Parkinson's disease. Int. Rev. Neurobiol. 168 , 1–31. 10.1016/bs.irn.2022.10.001 (2023). Zhang, Z. et al. Roles of Glutamate Receptors in Parkinson's Disease. Int. J. Mol. Sci. 20 10.3390/ijms20184391 (2019). Conn, P. J., Battaglia, G., Marino, M. J. & Nicoletti, F. Metabotropic glutamate receptors in the basal ganglia motor circuit. Nat. Rev. Neurosci. 6 , 787–798. 10.1038/nrn1763 (2005). Guimaraes, I. M., Carvalho, T. G., Ferguson, S. S., Pereira, G. S. & Ribeiro, F. M. The metabotropic glutamate receptor 5 role on motor behavior involves specific neural substrates. Mol. Brain . 8 , 24. 10.1186/s13041-015-0113-2 (2015). Tarhan, L. et al. Single Cell Portal: an interactive home for single-cell genomics data. bioRxiv 10.1101/2023.07.13.548886 (2023). Siletti, K. et al. Transcriptomic diversity of cell types across the adult human brain. Science 382 , eadd7046. 10.1126/science.add7046 (2023). Tasic, B. et al. Shared and distinct transcriptomic cell types across neocortical areas. Nature 563 , 72–78. 10.1038/s41586-018-0654-5 (2018). Zhang, Y. et al. Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse. Neuron 89 , 37–53. 10.1016/j.neuron.2015.11.013 (2016). Shcherbatyy, V. et al. A digital atlas of ion channel expression patterns in the two-week-old rat brain. Neuroinformatics 13 , 111–125. 10.1007/s12021-014-9247-0 (2015). Lein, E. S. et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 445 , 168–176. 10.1038/nature05453 (2007). Shin, H. et al. A Wireless Cortical Surface Implant for Diagnosing and Alleviating Parkinson's Disease Symptoms in Freely Moving Animals. Adv. Healthc. Mater. 14 , e2405179. 10.1002/adhm.202405179 (2025). Nam, J. et al. Cortical Stimulation-Based Transcriptome Shifts on Parkinson's Disease Animal Model. ASN Neuro . 17 , 2513881. 10.1080/17590914.2025.2513881 (2025). Kang, S. J. & Kaang, B. K. Metabotropic glutamate receptor dependent long-term depression in the cortex. Korean J. Physiol. Pharmacol. 20 , 557–564. 10.4196/kjpp.2016.20.6.557 (2016). Yang, S. et al. Integrity of mGluR-LTD in the associative/commissural inputs to CA3 correlates with successful aging in rats. J. Neurosci. 33 , 12670–12678. 10.1523/JNEUROSCI.1086-13.2013 (2013). Kemp, N. & Bashir, Z. I. Long-term depression: a cascade of induction and expression mechanisms. Prog Neurobiol. 65 , 339–365. 10.1016/s0301-0082(01)00013-2 (2001). Huber, K. M., Kayser, M. S. & Bear, M. F. Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 288 , 1254–1257. 10.1126/science.288.5469.1254 (2000). Kemp, N. & Bashir, Z. I. Induction of LTD in the adult hippocampus by the synaptic activation of AMPA/kainate and metabotropic glutamate receptors. Neuropharmacology 38 , 495–504. 10.1016/s0028-3908(98)00222-6 (1999). Shin, H. et al. A wireless cortical surface implant for diagnosing and alleviating Parkinson's disease symptoms in freely moving animals. Adv. Healthc. Mater. e2405179 10.1002/adhm.202405179 (2025). Cannon, W. B. & Rosenblueth, A. The supersensitivity of denervated structures; a law of denervation (Macmillan Co., 1949). Luscher, C. & Huber, K. M. Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65 , 445–459. 10.1016/j.neuron.2010.01.016 (2010). Mozafari, R., Karimi-Haghighi, S., Fattahi, M., Kalivas, P. & Haghparast, A. A review on the role of metabotropic glutamate receptors in neuroplasticity following psychostimulant use disorder. Prog Neuropsychopharmacol. Biol. Psychiatry . 124 , 110735. 10.1016/j.pnpbp.2023.110735 (2023). Madadi Asl, M., Vahabie, A. H. & Valizadeh, A. Dopaminergic Modulation of Synaptic Plasticity, Its Role in Neuropsychiatric Disorders, and Its Computational Modeling. Basic. Clin. Neurosci. 10 , 1–12. 10.32598/bcn.9.10.125 (2019). Abd-Elrahman, K. S., Sarasija, S. & Ferguson, S. S. G. The Role of Neuroglial Metabotropic Glutamate Receptors in Alzheimer's Disease. Curr. Neuropharmacol. 21 , 273–283. 10.2174/1570159X19666210916102638 (2023). Su, L. D., Wang, N., Han, J. & Shen, Y. Group 1 Metabotropic Glutamate Receptors in Neurological and Psychiatric Diseases: Mechanisms and Prospective. Neuroscientist 28 , 453–468. 10.1177/10738584211021018 (2022). Li, S. H., Colson, T. L., Abd-Elrahman, K. S. & Ferguson, S. S. G. Metabotropic Glutamate Receptor 5 Antagonism Reduces Pathology and Differentially Improves Symptoms in Male and Female Heterozygous zQ175 Huntington's Mice. Front. Mol. Neurosci. 15 , 801757. 10.3389/fnmol.2022.801757 (2022). Bertoglio, D. et al. Elevated Type 1 Metabotropic Glutamate Receptor Availability in a Mouse Model of Huntington's Disease: a Longitudinal PET Study. Mol. Neurobiol. 57 , 2038–2047. 10.1007/s12035-019-01866-5 (2020). Ribeiro, F. M., Vieira, L. B., Pires, R. G., Olmo, R. P. & Ferguson, S. S. Metabotropic glutamate receptors and neurodegenerative diseases. Pharmacol. Res. 115 , 179–191. 10.1016/j.phrs.2016.11.013 (2017). Ribeiro, F. M. et al. Metabotropic glutamate receptor 5 as a potential therapeutic target in Huntington's disease. Expert Opin. Ther. Tar . 18 , 1293–1304. 10.1517/14728222.2014.948419 (2014). Ribeiro, F. M. et al. Metabotropic Glutamate Receptor-Mediated Cell Signaling Pathways Are Altered in a Mouse Model of Huntington's Disease. J. Neurosci. 30 , 316–324. 10.1523/Jneurosci.4974-09.2010 (2010). Gubellini, P., Centonze, D., Tropepi, D., Bernardi, G. & Calabresi, P. Induction of corticostriatal LTP by 3-nitropropionic acid requires the activation of mGluR1/PKC pathway. Neuropharmacology 46 , 761–769. 10.1016/j.neuropharm.2003.11.021 (2004). Rammes, G., Hasenjager, A., Sroka-Saidi, K., Deussing, J. M. & Parsons, C. G. Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 metabotropic glutamate receptors in mediating the synaptotoxic effects of beta-amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices. Neuropharmacology 60 , 982–990. 10.1016/j.neuropharm.2011.01.051 (2011). Ng, A. N., Salter, E. W., Georgiou, J., Bortolotto, Z. A. & Collingridge, G. L. Amyloid-beta(1–42) oligomers enhance mGlu(5)R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling. iScience 26, 108412, (2023). 10.1016/j.isci.2023.108412 Li, S. et al. Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62 , 788–801. 10.1016/j.neuron.2009.05.012 (2009). Hsieh, H. et al. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52 , 831–843. 10.1016/j.neuron.2006.10.035 (2006). Jiang, X., Lin, W., Cheng, Y. & Wang, D. mGluR5 facilitates long-term synaptic depression in a stress-induced depressive mouse model. Can. J. Psychiatry . 65 , 347–355. 10.1177/0706743719874162 (2020). Li, M. X. et al. Increased Homer1-mGluR5 mediates chronic stress-induced depressive-like behaviors and glutamatergic dysregulation via activation of PERK-eIF2alpha. Prog Neuropsychopharmacol. Biol. Psychiatry . 95 , 109682. 10.1016/j.pnpbp.2019.109682 (2019). Pignatelli, M. et al. Enhanced mGlu5-receptor dependent long-term depression at the Schaffer collateral-CA1 synapse of congenitally learned helpless rats. Neuropharmacology 66 , 339–347. 10.1016/j.neuropharm.2012.05.046 (2013). Postnikova, T. Y. et al. Transient switching of NMDA-dependent long-term synaptic potentiation in CA3-CA1 hippocampal synapses to mGluR(1)-dependent potentiation after pentylenetetrazole-induced acute seizures in young rats. Cell. Mol. Neurobiol. 39 , 287–300. 10.1007/s10571-018-00647-3 (2019). Bernard, P. B., Castano, A. M., Bayer, K. U. & Benke, T. A. Necessary, but not sufficient: insights into the mechanisms of mGluR mediated long-term depression from a rat model of early life seizures. Neuropharmacology 84 , 1–12. 10.1016/j.neuropharm.2014.04.011 (2014). Kirschstein, T. et al. Loss of metabotropic glutamate receptor-dependent long-term depression via downregulation of mGluR5 after status epilepticus. J. Neurosci. 27 , 7696–7704. 10.1523/JNEUROSCI.4572-06.2007 (2007). Huber, K. M., Gallagher, S. M., Warren, S. T. & Bear, M. F. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl. Acad. Sci. U S A . 99 , 7746–7750. 10.1073/pnas.122205699 (2002). Nosyreva, E. D. & Huber, K. M. Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. J. Neurophysiol. 95 , 3291–3295. 10.1152/jn.01316.2005 (2006). Hou, L. et al. Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression. Neuron 51 , 441–454. 10.1016/j.neuron.2006.07.005 (2006). Michalon, A. et al. Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron 74 , 49–56. 10.1016/j.neuron.2012.03.009 (2012). Auerbach, B. D. & Bear, M. F. Loss of the fragile X mental retardation protein decouples metabotropic glutamate receptor dependent priming of long-term potentiation from protein synthesis. J. Neurophysiol. 104 , 1047–1051. 10.1152/jn.00449.2010 (2010). Kang, S. J. et al. Plasticity of metabotropic glutamate receptor-dependent long-term depression in the anterior cingulate cortex after amputation. J. Neurosci. 32 , 11318–11329. 10.1523/JNEUROSCI.0146-12.2012 (2012). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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1","display":"","copyAsset":false,"role":"figure","size":409396,"visible":true,"origin":"","legend":"\u003cp\u003eEvaluation of the 6-OHDA-induced hemi-parkinsonian rat model and extracellular field recordings of the M1 in Parkinson’s disease (PD) model animals. (\u003cstrong\u003ea\u003c/strong\u003e) Timeline of the experiments. (\u003cstrong\u003eb\u003c/strong\u003e) Visualization of contralateral rotation in 6-OHDA-induced hemi-parkinsonian rats after apomorphine administration, confirming the presence of 6-OHDA lesions in the PD model. (\u003cstrong\u003ec\u003c/strong\u003e) Comparison of latency to fall from the rod between the PD and Control (Ctrl) groups. (\u003cstrong\u003ed\u003c/strong\u003e) Representative images of tyrosine hydroxylase (TH)-positive staining in the substantia nigra pars compacta (SNc) and Striatum (STR) in the PD and Ctrl groups. (\u003cstrong\u003ee\u003c/strong\u003e) Schematic diagram of the experimental setup used to investigate synaptic responses. Field potential responses were observed in the presence of 10 μM 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX; AMPA receptor antagonist) and/or 1 μM tetrodotoxin (TTX; sodium channel blocker). Measurement of the field potential amplitude at peak latency, showing a 60% reduction upon NBQX application with complete abolishment following additional TTX administration. All data are presented as the mean ± standard deviation. **P \u0026lt; 0.01, ****P \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"Picture1.png","url":"https://assets-eu.researchsquare.com/files/rs-7634193/v1/0890cdcf684f0937fcd97c0e.png"},{"id":93694682,"identity":"92b4e647-6a01-4a27-ac3d-02c2a5ab25c3","added_by":"auto","created_at":"2025-10-16 14:34:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":460945,"visible":true,"origin":"","legend":"\u003cp\u003eGroup I metabotropic glutamate receptor (mGluR)-dependent and NMDA receptor (NMDAR)-dependent long-term depression (LTD) in the hemi-parkinsonian rat primary motor cortexsurface. (\u003cstrong\u003ea\u003c/strong\u003e) mGluR-dependent LTD. Normalized fEPSP responses following paired-pulse low-frequency stimulation(pp-LFS) in Parkinson’s disease (PD) and Control (Ctrl) group animals. LTD was observed in both groups; however, the extent of LTD was notably reduced in the PD group compared with the Ctrl group. LTD in the PD group was blocked by only 100 μM AP5 (NMDAR antagonist). Co-application of the mGluR antagonists MPEP (10 μM) and LY 367385 (100 μM) with AP5 fully suppressed LTD in the Ctrl group, indicating that the mGluR pathways were fully functional and contributed significantly to synaptic plasticity. These findings suggest a potential deficit in mGluR function that contributes to the impaired synaptic plasticity in PD. (\u003cstrong\u003eb\u003c/strong\u003e) NMDAR-dependent LTD. Normalized fEPSP responses following single-pulse (sp)-LFS in the PD and Ctrl groups. LTD is shown to be induced in both groups, but no significant differences are observed between the groups. All data are presented as the mean ± standard deviation. *P \u0026lt; 0.05, **P\u0026lt; 0.01, ***P \u0026lt; 0.005, ****P \u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"Picture2.png","url":"https://assets-eu.researchsquare.com/files/rs-7634193/v1/3258157b17481dc664fd269c.png"},{"id":93695737,"identity":"f3c70dfb-fff8-4332-90c0-d3c029aeaa2e","added_by":"auto","created_at":"2025-10-16 14:42:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":507619,"visible":true,"origin":"","legend":"\u003cp\u003eIntrinsic membrane properties of layer 2/3 pyramidal neurons in the primary motor cortex are preserved in Parkinson’s disease (PD) model animals. (\u003cstrong\u003ea\u003c/strong\u003e) Representative traces showing the membrane potential responses to step current injections (-400, -200, +300, and +600 pA) in the Control (Ctrl; left, gray) and PD (right, light red) neurons. (\u003cstrong\u003eb\u003c/strong\u003e) Resting membrane potential (RMP) measured 3 min after break-in. (\u003cstrong\u003ec\u003c/strong\u003e) Input resistance (R\u003csub\u003ein\u003c/sub\u003e) determined from voltage deflections at a -100 pA current injection. (\u003cstrong\u003ed\u003c/strong\u003e) Firing frequency in response to increasing current injections from 0 to +800 pA in 100-pA steps. The number of action potentials (APs) increased proportionally with the current intensity. \u003cstrong\u003e(e)\u003c/strong\u003e Representative traces of APs (top) and their first derivatives (dV/dt, bottom) recorded from Ctrl (gray) and PD (light red) neurons. Quantification of the AP threshold, amplitude, half-width, and maximum rise/decay rate and the afterhyperpolarization (AHP) amplitude. (\u003cstrong\u003ef\u003c/strong\u003e) Spontaneous excitatory postsynaptic currents (sEPSCs) recorded at a -70 mV holding potential. Representative traces from Ctrl (top, gray) and PD neurons (bottom, light red). The sEPSC amplitude and frequency did not significantly differ between the groups. All data are presented as the mean ± standard deviation. *P \u0026lt; 0.05, **P \u0026lt; 0.01.\u003c/p\u003e","description":"","filename":"Picture3.png","url":"https://assets-eu.researchsquare.com/files/rs-7634193/v1/cdc2260f322ebde839cc3b4b.png"},{"id":93694018,"identity":"cc3d4cc2-15e9-45b2-8194-3c5e874ea47d","added_by":"auto","created_at":"2025-10-16 14:26:33","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":130718,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic model of the changes in group I metabotropic glutamate receptor (mGluR)-driven long-term synaptic plasticity in the superficial primary motor cortices (M1) of Parkinson’s disease (PD) model animals. mGluR\u003csub\u003e1/5\u003c/sub\u003e-mediated long-term potentiation is significantly stronger in PD rats than in controls\u003csup\u003e29\u003c/sup\u003e, whereas mGluR\u003csub\u003e1/5\u003c/sub\u003e-long-term depression is substantially weaker in PD rats. NMDA receptor (NMDAR)-dependent synaptic modulation is unaffected in the M1 layer 1/2 of PD rats.\u003c/p\u003e","description":"","filename":"Picture4.png","url":"https://assets-eu.researchsquare.com/files/rs-7634193/v1/4b0522529d0a53f6eea13e10.png"},{"id":94988358,"identity":"ea18de12-3eac-4110-b40a-c32a50203e09","added_by":"auto","created_at":"2025-11-03 07:08:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2557137,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7634193/v1/c198dedf-df97-4d0f-8f57-7163b60eb9f6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eAltered mGluR\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e1/5\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e-driven plasticity in the motor cortical surface as a biomarker for Parkinson’s disease\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eParkinson\u0026rsquo;s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons, primarily in the substantia nigra pars compacta (SNc), which leads to profound disruptions in motor function\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. A major consequence of this nigral degeneration is a weakening of motor command and control both to and from the primary motor cortex (M1). As the M1 is crucial for executing precise motor commands, disruptions in this area contribute directly to the motor deficits observed in PD\u003csup\u003e5\u0026ndash;8\u003c/sup\u003e. In particular, the surface layers of sensorimotor cortices are thought to determine cortical map organization, influence associative information processing, and play a crucial role in learning\u003csup\u003e\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14 CR15\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Although the motor cortex surface is relatively less understood, identifying pathological signatures in this region may provide novel targets for therapeutic interventions against PD.\u003c/p\u003e\u003cp\u003eReports have consistently described altered synaptic plasticity of the M1 in PD\u003csup\u003e6,7,17\u003c/sup\u003e. Both long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity are impaired in patients with PD\u003csup\u003e18\u003c/sup\u003e. Metabotropic glutamate receptors (mGluRs) are key modulators of synaptic plasticity in sensorimotor cortices, and their dysfunction is increasingly recognized as a factor contributing to PD-related motor impairments\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Group I mGluRs, namely mGluR\u003csub\u003e1\u003c/sub\u003e and mGluR\u003csub\u003e5\u003c/sub\u003e, not only counteract dopaminergic signaling in the healthy basal ganglia but also may influence the progression of dopaminergic degeneration in PD models\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Furthermore, selective blockade of mGluR\u003csub\u003e5\u003c/sub\u003e in the M1 reduced spontaneous locomotion and motor coordination\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. These findings strongly suggest a crucial role of mGluRs in motor function, given that group I mGluRs are expressed in most neurons across various animal species\u003csup\u003e\u003cspan additionalcitationids=\"CR25 CR26 CR27 CR28\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Previously, we demonstrated the enhancement of mGluR\u003csub\u003e1/5\u003c/sub\u003e-driven LTP at the M1 surface in a PD model\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e and provided transcriptomic evidence showing that genes associated with synaptic plasticity are significantly altered in the M1 under PD conditions\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. However, it remains unknown whether mGluR-mediated LTD also plays a role in PD.\u003c/p\u003e\u003cp\u003eIn this study, we aimed to investigate mGluR-driven synaptic depression within the M1 of a 6-hydroxydopamine (6-OHDA)-induced PD rat model, with a specific focus on the role of mGluRs. Our findings demonstrate the strong involvement of dysregulated mGluR activity with abnormal motor behavior in PD, thereby highlighting the critical role of mGluRs in PD pathology.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eBehavioral validation of the hemi-parkinsonian model\u003c/h2\u003e\u003cp\u003eThe PD model was generated via the unilateral administration of 6-OHDA to rats. Two weeks later, the rats were subjected to apomorphine-induced rotation and rotarod tests for behavioral confirmation of PD symptoms (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). In the apomorphine-induced rotation test, PD rats showed a significant increase in rotating behavior compared with control (Ctrl) rats, which exhibited minimal rotational behavior (Ctrl: 1.50\u0026thinsp;\u0026plusmn;\u0026thinsp;4.36, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6 vs. PD: 121.00\u0026thinsp;\u0026plusmn;\u0026thinsp;18.27, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9; \u003cem\u003et\u003c/em\u003e(8.890) = -6.354, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, independent sample \u003cem\u003et\u003c/em\u003e-test) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). The rotarod test also revealed significant motor impairments in the PD rats. After normalizing the data to the pre-test level, the latency to fall off the rotarod was decreased in the PD group but increased in the Ctrl group (Ctrl: 150.10% \u0026plusmn; 18.94%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;4 vs. PD: 72.68% \u0026plusmn; 10.10%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5; \u003cem\u003et\u003c/em\u003e(7)\u0026thinsp;=\u0026thinsp;3.722, P\u0026thinsp;=\u0026thinsp;0.004, independent sample \u003cem\u003et\u003c/em\u003e-test; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). These behavioral observations demonstrate the successful establishment of the PD model. To additionally confirm the loss of dopaminergic neurons after 6-OHDA administration, tyrosine hydroxylase (TH) immunostaining was performed 1 week after completion of the behavioral tests. In PD rats, the TH-positive area in the 6-OHDA-injected hemisphere (normalized to the untreated hemisphere) decreased significantly in both the SNc and Striatum (STR) (SNc-Ctrl: 96.58% \u0026plusmn; 4.03%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5 vs. SNc-PD: 13.02% \u0026plusmn; 5.60%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5; \u003cem\u003et\u003c/em\u003e(8)\u0026thinsp;=\u0026thinsp;12.107, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, independent sample \u003cem\u003et\u003c/em\u003e-test; STR-Ctrl: 101.64% \u0026plusmn; 2.05%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5 vs. STR-PD: 0.53% \u0026plusmn; 0.13%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5; \u003cem\u003et\u003c/em\u003e(4.031)\u0026thinsp;=\u0026thinsp;49.344, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, independent sample \u003cem\u003et\u003c/em\u003e-test; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed). These results confirm that dopamine lesions caused the motor defects in this PD rat model.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eNext, we verified the presence of glutamatergic synapses in the M1 surface. Extracellular field recording was performed 3 weeks after 6-OHDA injection. Stimulation and recording electrodes were placed on the M1 layer 1/2. Synaptic responses were reduced by the bath application of 2,3-dioxo-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX, 10 \u0026micro;M), an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist. Subsequent application of tetrodotoxin (TTX, 1 \u0026micro;M) nearly abolished the synaptic response, confirming that glutamatergic synapses exist in the cortical surface of M1 (PD: 100.00% \u0026plusmn; 0.00%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5 vs. NBQX: 38.39% \u0026plusmn; 8.45%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5 vs. NBQX\u0026thinsp;+\u0026thinsp;TTX: 11.55% \u0026plusmn; 1.87%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5; \u003cem\u003eF\u003c/em\u003e(2, 12)\u0026thinsp;=\u0026thinsp;82.455, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, one-way ANOVA with Bonferroni\u0026rsquo;s post hoc test; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ee). These findings are consistent with those of our previous study\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSelective impairment of mGluR-dependent LTD in PD\u003c/h3\u003e\n\u003cp\u003eTo investigate the contribution of mGluRs to LTD in the M1 surface, we applied two previously well-established protocols for inducing LTD in cortical slices: (i) mGluR-dependent LTD (or mGluR-LTD) induced by paired-pulse low-frequency stimulation (pp-LFS; 900 pairs of pulses delivered at 1 Hz with 50-ms inter-pulse intervals), and (ii) N-methyl-D-aspartate receptor (NMDAR)-dependent LTD (i.e., NMDAR-LTD) induced by single-pulse low-frequency stimulation (sp-LFS; 900 single pulses at 1 Hz)\u003csup\u003e\u003cspan additionalcitationids=\"CR32 CR33 CR34\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. We first verified that pp-LFS activated mGluRs but not NMDARs. Bath application of (2R)-amino-5-phosphonovaleric acid (AP5, 100 \u0026micro;M), an NMDAR antagonist, had little effect on pp-LFS-induced LTD in the Ctrl M1 (Ctrl: 75.70% \u0026plusmn; 8.084%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8 vs. Ctrl AP5: 80.26% \u0026plusmn; 10.01%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11, \u003cem\u003et\u003c/em\u003e(17) = -1.060, P\u0026thinsp;=\u0026thinsp;0.152, independent sample \u003cem\u003et\u003c/em\u003e-test; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The additional administration of 2-methyl-6-phenylethynyl-pyridine (MPEP, 10 \u0026micro;M) an mGluR\u003csub\u003e5\u003c/sub\u003e antagonist, and (S)-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acid (LY 367385; LY, 100 \u0026micro;M), an mGluR\u003csub\u003e1\u003c/sub\u003e antagonist, completely eliminated LTD at 60 minutes post-induction, further confirming that pp-LFS-induced LTD in the M1 surface is driven by group I mGluRs under naive conditions (Ctrl: 75.70% \u0026plusmn; 8.084%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8 vs. Ctrl AP5: 80.26% \u0026plusmn; 10.01%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11 vs. Ctrl AP5\u0026thinsp;+\u0026thinsp;MPEP\u0026thinsp;+\u0026thinsp;LY: 102.5% \u0026plusmn; 20.74%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9; \u003cem\u003eF\u003c/em\u003e(2, 25)\u0026thinsp;=\u0026thinsp;9.305, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, one-way ANOVA). We next investigated whether PD affected mGluR-LTD in the M1, applying AP5 to prevent NMDAR activation. The finding that AP5 alone eliminated LTD (PD: 87.60% \u0026plusmn; 10.56%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10 vs. PD AP5: 100.2% \u0026plusmn; 20.34%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6; \u003cem\u003et\u003c/em\u003e(18) = -1.741, P\u0026thinsp;=\u0026thinsp;0.049, independent sample \u003cem\u003et\u003c/em\u003e-test) revealed the absence of mGluR-LTD in the PD M1 surface.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTo further examine if PD also affected NMDAR-LTD, we applied sp-LFS, which induced LTD at the M1 surface in both Ctrl and PD slices; AP5 completely blocked LTD in both slices (Ctrl: 83.12% \u0026plusmn; 15.17%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;19 vs. Ctrl AP5: 103.8% \u0026plusmn; 18.55%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8; \u003cem\u003et\u003c/em\u003e(25) = -3.030, P\u0026thinsp;=\u0026thinsp;0.003, independent sample \u003cem\u003et\u003c/em\u003e-test; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb; PD: 82.69% \u0026plusmn; 12.09%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;18 vs. PD AP5: 105.3% \u0026plusmn; 10.76%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;6; \u003cem\u003et\u003c/em\u003e(22) = -4.068, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, independent sample \u003cem\u003et\u003c/em\u003e-test). No significant difference in NMDAR-LTD amplitude was observed between the Ctrl and PD slices (Ctrl: 83.12% \u0026plusmn; 15.17%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;19, PD: 82.69% \u0026plusmn; 12.09%, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;18; \u003cem\u003et\u003c/em\u003e(35)\u0026thinsp;=\u0026thinsp;0.095, P\u0026thinsp;=\u0026thinsp;0.463, independent sample \u003cem\u003et\u003c/em\u003e-test). Thus, PD does not appear to affect NMDAR-driven LTD; it is associated with changes in mGluR\u003csub\u003e1/5\u003c/sub\u003e-LTD, but not NMDAR-LTD, at the M1 surface.\u003c/p\u003e\n\u003ch3\u003ePreserved intrinsic properties with altered action potential (AP) kinetics in PD neurons\u003c/h3\u003e\n\u003cp\u003eTo determine whether PD pathology affects the intrinsic membrane properties of M1 pyramidal neurons, we conducted whole-cell patch-clamp recordings of layer 2 neurons. Representative traces (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea) illustrate that Ctrl and PD neurons exhibited similar firing patterns in response to step current injections. The resting membrane potential (RMP), measured 3 minutes after break-in, did not differ significantly between the groups (Ctrl: -80.82\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11 vs. PD: -79.80\u0026thinsp;\u0026plusmn;\u0026thinsp;0.94, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;8; \u003cem\u003et\u003c/em\u003e(9.391) = -1.004, P\u0026thinsp;=\u0026thinsp;0.170, independent sample \u003cem\u003et\u003c/em\u003e-test; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). The input resistance (R\u003csub\u003ein\u003c/sub\u003e), assessed at -100 pA hyperpolarizing current injection, also did not differ significantly between the groups (Ctrl: 60.86\u0026thinsp;\u0026plusmn;\u0026thinsp;5.17, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11 vs. PD: 59.46\u0026thinsp;\u0026plusmn;\u0026thinsp;3.37, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10; \u003cem\u003et\u003c/em\u003e(19)\u0026thinsp;=\u0026thinsp;0.221, P\u0026thinsp;=\u0026thinsp;0.414, independent sample \u003cem\u003et\u003c/em\u003e-test; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec). Neuronal excitability was quantified as the number of APs generated in response to depolarizing current steps (0 to +\u0026thinsp;800 pA, 100-pA increments). Both Ctrl and PD neurons displayed a graded increase in the firing frequency, but there was no detectable difference between the groups (\u003cem\u003eF\u003c/em\u003e(17, 1)\u0026thinsp;=\u0026thinsp;0.047, P\u0026thinsp;=\u0026thinsp;1.000, two-way ANOVA; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eNumber of action potentials arising in layer 2/3 pyramidal neurons in response to increasing current injections. Related to Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed. Ctrl, Control; PD, Parkinson\u0026rsquo;s disease.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"9\" nameend=\"c10\" namest=\"c2\"\u003e\u003cp\u003eCurrent injection (pA)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGroup (\u003cem\u003en\u003c/em\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e200\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e300\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e400\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e500\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003e600\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003e700\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003e800\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCtrl (10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e0.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e0.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e0.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e3.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e7.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e\u003cp\u003e10.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c8\"\u003e\u003cp\u003e14.38\u0026thinsp;\u0026plusmn;\u0026thinsp;1.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e\u003cp\u003e17.88\u0026thinsp;\u0026plusmn;\u0026thinsp;1.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c10\"\u003e\u003cp\u003e21.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePD (10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e0.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e0.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e0.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e2.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e6.70\u0026thinsp;\u0026plusmn;\u0026thinsp;0.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e\u003cp\u003e10.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c8\"\u003e\u003cp\u003e14.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c9\"\u003e\u003cp\u003e17.70\u0026thinsp;\u0026plusmn;\u0026thinsp;0.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c10\"\u003e\u003cp\u003e20.72\u0026thinsp;\u0026plusmn;\u0026thinsp;0.37\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eWe additionally analyzed various parameters of the AP waveform (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ee). Representative traces of APs and their first derivatives (dV/dt) are shown for Ctrl and PD neurons. The threshold voltage (Ctrl\u003csub\u003ethreshold\u003c/sub\u003e: -31.90\u0026thinsp;\u0026plusmn;\u0026thinsp;1.11, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9 vs. PD\u003csub\u003ethreshold\u003c/sub\u003e: -33.29\u0026thinsp;\u0026plusmn;\u0026thinsp;1.16, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9; \u003cem\u003et\u003c/em\u003e(16)\u0026thinsp;=\u0026thinsp;0.864, P\u0026thinsp;=\u0026thinsp;0.200, independent sample \u003cem\u003et\u003c/em\u003e-test) and AP amplitude (Ctrl\u003csub\u003eamplitude\u003c/sub\u003e: 78.81\u0026thinsp;\u0026plusmn;\u0026thinsp;1.52, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9 vs. PD\u003csub\u003eamplitude\u003c/sub\u003e: 77.23\u0026thinsp;\u0026plusmn;\u0026thinsp;2.20, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9; \u003cem\u003et\u003c/em\u003e(16)\u0026thinsp;=\u0026thinsp;0.651, P\u0026thinsp;=\u0026thinsp;0.282, independent sample \u003cem\u003et\u003c/em\u003e-test) did not significantly differ between the groups. However, the AP half-width was significantly lower in PD neurons than in Ctrl neurons, indicating sharper spikes (Ctrl\u003csub\u003ehalf\u0026minus;width\u003c/sub\u003e: 1.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9 vs. PD\u003csub\u003ehalf\u0026minus;width\u003c/sub\u003e: 1.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9; \u003cem\u003et\u003c/em\u003e(10.816)\u0026thinsp;=\u0026thinsp;2.774, P\u0026thinsp;=\u0026thinsp;0.009, independent sample \u003cem\u003et\u003c/em\u003e-test). Although the maximum rise rate was unaffected (Ctrl\u003csub\u003emaximum rise rate\u003c/sub\u003e: 177.10\u0026thinsp;\u0026plusmn;\u0026thinsp;4.32, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9 vs. PD\u003csub\u003emaximum rise rate\u003c/sub\u003e: 168.56\u0026thinsp;\u0026plusmn;\u0026thinsp;7.02, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9; \u003cem\u003et\u003c/em\u003e(16)\u0026thinsp;=\u0026thinsp;1.036, P\u0026thinsp;=\u0026thinsp;0.158, independent sample \u003cem\u003et\u003c/em\u003e-test), the maximum decay rate was faster in PD (vs. Ctrl) neurons (Ctrl\u003csub\u003emaximum decay rate\u003c/sub\u003e: -46.22\u0026thinsp;\u0026plusmn;\u0026thinsp;2.39, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9 vs. PD\u003csub\u003emaximum decay rate\u003c/sub\u003e: -53.37\u0026thinsp;\u0026plusmn;\u0026thinsp;1.70, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9; \u003cem\u003et\u003c/em\u003e(16)\u0026thinsp;=\u0026thinsp;2.436, P\u0026thinsp;=\u0026thinsp;0.013, independent sample \u003cem\u003et\u003c/em\u003e-test), consistent with accelerated repolarization. The amplitude of afterhyperpolarization (AHP) did not significantly differ between the groups (Ctrl\u003csub\u003eAHP\u003c/sub\u003e: 12.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.65, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9 vs. PD\u003csub\u003eAHP\u003c/sub\u003e: 14.71\u0026thinsp;\u0026plusmn;\u0026thinsp;1.34, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;9; \u003cem\u003et\u003c/em\u003e(11.582) = -1.279, P\u0026thinsp;=\u0026thinsp;0.113, independent sample \u003cem\u003et\u003c/em\u003e-test).\u003c/p\u003e\u003cp\u003eFinally, we quantified the spontaneous excitatory synaptic inputs by recording spontaneous excitatory postsynaptic currents (sEPSCs) at a holding potential of -70 mV. Representative traces and group analyses revealed no significant alterations in either the sEPSC amplitude (Ctrl\u003csub\u003eAmplitude\u003c/sub\u003e: 28.48, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11; PD\u003csub\u003eAmplitude\u003c/sub\u003e: 28.71\u0026thinsp;\u0026plusmn;\u0026thinsp;1.50, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7; \u003cem\u003et\u003c/em\u003e(16) = -0.026, P\u0026thinsp;=\u0026thinsp;0.490, independent sample \u003cem\u003et\u003c/em\u003e-test) or frequency (Ctrl\u003csub\u003eFrequency\u003c/sub\u003e: 2.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11; PD\u003csub\u003eFrequency\u003c/sub\u003e: 3.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.63, \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;7; \u003cem\u003et\u003c/em\u003e(16) = -0.599, P\u0026thinsp;=\u0026thinsp;0.279, independent sample \u003cem\u003et\u003c/em\u003e-test) in PD neurons relative to Ctrl neurons (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ef). Altogether, these results indicate that the intrinsic electrophysiological properties and excitatory synaptic transmission of layer 2 M1 pyramidal neurons are not significantly altered in our PD rat model. The impaired cortical plasticity observed in PD is therefore unlikely to arise from changes in neuronal excitability or excitatory inputs under unstimulated conditions. Nonetheless, the sharper AP kinetics in PD may contribute to abnormal motor function and neuroplasticity when stimulated.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we investigated the dynamics of synaptic LTD in the superficial layers of the M1 of 6-OHDA PD model rats, using extracellular field recording and whole-cell patch-clamp recording. Field recording data revealed that PD is associated with a pronounced shift in mGluR\u003csub\u003e1/5\u003c/sub\u003e-driven synaptic plasticity, characterized by enhanced mGluR-dependent LTP and reduced mGluR-LTD. Patch-clamp data further demonstrated that the intrinsic neuronal properties and spontaneous EPSCs were largely preserved in the M1 layer 2/3 neurons of PD model animals. However, we observed significantly altered AP kinetics in PD neurons, such as narrower spike half-widths and accelerated repolarization, which indicate sharper firing activity accompanied by an increase in synaptic weight. Together with our previous report\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e, these results indicate that dopaminergic degeneration leads to an overall shift in mGluR\u003csub\u003e1/5\u003c/sub\u003e-driven synaptic plasticity toward increased synaptic weight at the M1 surface\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). This shift may reflect sensorimotor homeostasis that stabilizes cortical function and motor learning in response to denervation of the M1 from basal ganglia inputs\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eOur findings also reveal that NMDAR-dependent mechanisms in the superficial M1 layer did not change significantly under PD conditions. This result highlights the importance of mGluR signaling in PD, consistent with several reports of interactions between dopamine and mGluR-LTD in the basal ganglia motor circuit\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Partial depletion of dopaminergic neurons is associated with reduced mGluR\u003csub\u003e1/5\u003c/sub\u003e-dependent plasticity in the indirect pathway\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e, and our data extend the body of evidence by showing that the shifts in mGluR-LTD and mGluR-LTP in the M1 surface are closely associated with dyskinesia. Abnormal mGluR-dependent plasticity is not unique to PD. mGluR dysfunction has been implicated in other neurodegenerative and neuropsychiatric disorders, including Huntington\u0026rsquo;s disease, Alzheimer\u0026rsquo;s disease, epilepsy, and depression\u003csup\u003e\u003cspan additionalcitationids=\"CR42 CR43 CR44 CR45 CR46\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). These convergent findings emphasize the broader significance of mGluRs in circuit regulation and disease progression. Nonetheless, our findings do not conclusively prove a cause-and-effect relationship between sensorimotor deficits and altered synaptic plasticity and AP kinetics.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eChanges in metabotropic glutamate receptor (mGluR)-mediated long-term synaptic plasticity are associated with various neurodegenerative and neurological diseases. mGluR-driven long-term potentiation (LTP) or long-term depression (LTD) can be induced in various regions of the brain (induction methods shown in brackets) and are suppressed or enhanced under disease conditions. \u0026darr; indicates suppression, \u0026uarr; indicates enhancement of mGluR-LTP or mGluR-LTD in disease models. HFS, high frequency stimulation; KO, knockout; LFS, low-frequency stimulation; MPEP, 2-methyl-6-phenylethynyl-pyridine; pp, paired-pulse; TBS, theta burst stimulation; DHPG, 3,5-Dihydroxyphenylglycine; ACC, anterior cingulate cortex.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eDisease\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eAnimal\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eRecording site\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eSynaptic modulation\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLTP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLTD\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eParkinson\u0026rsquo;s disease\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e(This work)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSprague-Dawley rat\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMotor cortex\u003c/p\u003e\u003cp\u003esuperficial layer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026uarr;\u003c/p\u003e\u003cp\u003e(HFS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003cp\u003e(pp-LFS / LFS)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHearing loss/tinnitus\u003c/b\u003e\u003csup\u003e10\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC57BL/6 mouse\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAuditory cortex superficial layer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026darr; or \u0026uarr;\u003c/p\u003e\u003cp\u003e(Decreased pp-LFS-LTP/ increased TBS-LTP)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHuntington\u0026rsquo;s disease\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWistar rat\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCorticostriatal fibers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026uarr;\u003c/p\u003e\u003cp\u003e(3-NP)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAlzheimer\u0026rsquo;s disease\u003c/b\u003e\u003csup\u003e\u003cspan additionalcitationids=\"CR50 CR51\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC57BL/6 mouse\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHippocampus CA3-CA1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003cp\u003e(HFS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; or \u0026darr;\u003c/p\u003e\u003cp\u003e(DHPG / LFS)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDepression\u003c/b\u003e\u003csup\u003e\u003cspan additionalcitationids=\"CR54\" citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC57BL/6 mouse\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHippocampus CA3-CA1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr;\u003c/p\u003e\u003cp\u003e(pp-LFS / DHPG)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEpilepsy / seizures\u003c/b\u003e\u003csup\u003e56\u0026ndash;58\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWistar rat\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHippocampus CA3-CA1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026uarr;\u003c/p\u003e\u003cp\u003e(TBS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003cp\u003e(pp-LFS)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFragile X syndrome\u003c/b\u003e\u003csup\u003e\u003cspan additionalcitationids=\"CR60 CR61 CR62\" citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eFmr1\u003c/em\u003e KO mouse\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHippocampus CA3-CA1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAffects LTP priming\u003c/p\u003e\u003cp\u003e(DHPG\u0026thinsp;+\u0026thinsp;100 Hz HFS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr;\u003c/p\u003e\u003cp\u003e(pp-LFS / DHPG)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eChronic pain\u003c/b\u003e\u003csup\u003e\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC57BL/6 mouse\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eACC layer V-II/III, V-V/VI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003cp\u003e(DHPG\u0026thinsp;+\u0026thinsp;MPEP/LFS)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eOverall, our study highlights the significant contribution of group I mGluRs to the homeostatic regulation of synaptic plasticity in the M1 superficial layer. Abnormal mGluR\u003csub\u003e1/5\u003c/sub\u003e-LTP and LTD in this region are closely associated with sensorimotor deficits in PD and thus may represent promising targets for therapeutic intervention. Future research should focus on identifying the neuronal populations that mediate mGluR\u003csub\u003e1/5\u003c/sub\u003e-driven cortical surface plasticity, mapping the specific circuits involved, and clarifying underlying cellular mechanisms such as postsynaptic AMPAR trafficking, intracellular calcium signaling, local mRNA translation, and presynaptic neurotransmitter release.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eAnimals\u003c/h2\u003e\u003cp\u003eSix-week-old male Sprague-Dawley rats were housed under a 12-hour light/dark cycle in a temperature-controlled facility (25\u0026deg;C) and allowed access to food and water \u003cem\u003ead libitum\u003c/em\u003e. All animal procedures were approved by the Institutional Animal Care and Use Committee at Incheon National University (Approval Code: INU-ANIM-2024-14) and carried out in accordance with relevant regulations. This study also adhered to ARRIVE guidelines.\u003c/p\u003e\u003cp\u003e\u003cb\u003e6-OHDA-induced hemi-parkinsonian rat model\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTo generate the hemi-parkinsonian PD rat model, dopaminergic neuron degeneration was induced through the stereotaxic administration of 6-OHDA (dissolved in normal saline with 0.02% ascorbic acid) into the medial forebrain bundle. The animals were anesthetized by isoflurane inhalation (2%), and a burr hole was created in one hemisphere at -3.84 mm anterior and \u0026minus;\u0026thinsp;1.4 mm lateral to the bregma. 6-OHDA was injected at a depth of 8.5 mm below the dura mater and an infusion rate of 0.5 \u0026micro;L/minute for 8 minutes using a Hamilton syringe equipped with a micropump injector (26G needle). The 6-OHDA-administered hemisphere (PD) was compared with the contralateral hemisphere (Ctrl).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eApomorphine-induced rotation test\u003c/h3\u003e\n\u003cp\u003eTo screen for 6-OHDA-induced dopamine depletion, rats were administered apomorphine (0.5 mg/kg in 0.1% ascorbic acid, subcutaneous) and placed individually in a 30-cm-diameter cylinder. Rotating behavior was recorded using a digital video camera. The number of rotations during a 30-minute observation period was manually counted. The net number of rotations was calculated as the number of contralateral rotations (away from the lesioned side) minus the number of ipsilateral rotations. Animals exhibiting at least three net contralateral rotations per minute were considered to display PD symptoms.\u003c/p\u003e\n\u003ch3\u003eRotarod test\u003c/h3\u003e\n\u003cp\u003eThe animals were trained to walk on a rotarod apparatus (Ugo Basile, Italy) prior to testing. Fourteen days after 6-OHDA administration, rats were subjected to the rotarod test at a rotation speed of 10 rpm for at least 180 seconds. The speed was gradually increased at a rate of 1 rpm every 6 seconds, and the latency to fall from the rod was recorded in two trials per rat. Data are presented as the ratio of the latency to fall after 6-OHDA administration to that before 6-OHDA administration (%).\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eImmunohistochemistry\u003c/h2\u003e\u003cp\u003eRats were deeply anesthetized via isoflurane inhalation (2%) and perfused transcardially with phosphate-buffered saline (PBS) and 4% paraformaldehyde (PFA). The brains were dissected and submerged in 4% PFA for 24 hours at 4\u0026deg;C, then submerged in 30% sucrose. Then, the brains were cut into 50-\u0026micro;m-thick coronal frozen sections using a cryostat (CM1520, Leica Biosystems, Germany). For TH staining, free-floating sections were washed with 0.3% Triton X-100 in PBS for 30 minutes, then incubated overnight with a rabbit anti-TH antibody (1:1,000 dilution, AB152, RRID: AB_390204, Millipore, USA). After washing with PBS, the sections were incubated with a biotinylated secondary anti-rabbit antibody (1:200 dilution, MP-7401, RRID: AB_2336529, Vector Labs, USA) for 1 hour. Antibody labeling was visualized via incubation with 3,3-diaminobenzidine for 3\u0026ndash;5 minutes, and the sections were mounted on aminosilane-coated slides. The area of TH-positive staining in the ipsilateral hemisphere was normalized to that of the contralateral hemisphere (100%).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eBrain slice preparation\u003c/h2\u003e\u003cp\u003ePrimary motor cortical slices were collected from hemi-parkinsonism rats. The animals were deeply anesthetized with 2% isoflurane, and the brains were rapidly removed into chilled, oxygenated dissection buffer. For extracellular field recording, slices were prepared in a sucrose-based slicing buffer containing 75.0 mM sucrose, 25.0 mM glucose, 87.0 mM NaCl, 2.5 mM KCl, 1.3 mM NaH\u003csub\u003e2\u003c/sub\u003ePO\u003csub\u003e4\u003c/sub\u003e, 25.0 mM NaHCO\u003csub\u003e3\u003c/sub\u003e, 7.0 mM MgCl\u003csub\u003e2\u003c/sub\u003e, and 0.5 mM CaCl\u003csub\u003e2\u003c/sub\u003e. For whole-cell patch-clamp recording, slices were prepared in a choline-based slicing buffer containing 20.0 mM glucose, 110.0 mM choline chloride, 2.5 mM KCl, 1.2 mM NaH\u003csub\u003e2\u003c/sub\u003ePO\u003csub\u003e4\u003c/sub\u003e, 7.0 mM MgCl\u003csub\u003e2\u003c/sub\u003e, and 0.5 mM CaCl\u003csub\u003e2\u003c/sub\u003e.\u003c/p\u003e\u003cp\u003eCoronal motor cortical slices were cut using a Leica VT1200S vibratome at a 400-\u0026micro;m thickness for field recordings and 300-\u0026micro;m thickness for patch-clamp recordings. After cutting, the slices were transferred to artificial cerebrospinal fluid (ACSF; 25.0 mM glucose, 125.0 mM NaCl, 2.5 mM KCl, 1.3 mM NaH\u003csub\u003e2\u003c/sub\u003ePO\u003csub\u003e4\u003c/sub\u003e, 25.0 mM NaHCO\u003csub\u003e3\u003c/sub\u003e, 1.0 mM MgCl\u003csub\u003e2\u003c/sub\u003e, and 2.0 mM CaCl\u003csub\u003e2\u003c/sub\u003e for field recordings; 20.0 mM glucose, 124.0 mM NaCl, 2.5 mM KCl, 1.0 mM NaH\u003csub\u003e2\u003c/sub\u003ePO\u003csub\u003e4\u003c/sub\u003e, 26.2 mM NaHCO\u003csub\u003e3\u003c/sub\u003e, 1.3 mM MgCl\u003csub\u003e2\u003c/sub\u003e, and 2.5 mM CaCl\u003csub\u003e2\u003c/sub\u003e for patch recordings), which was continuously bubbled with 95% O\u003csub\u003e2\u003c/sub\u003e/5% CO\u003csub\u003e2\u003c/sub\u003e. All slices were incubated at 32\u0026deg;C for 12 minutes and allowed to recover for 1 h at room temperature, then transferred to a submersion-type recording chamber perfused with oxygenated ACSF at 31\u0026ndash;32\u0026deg;C.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eExtracellular field recording\u003c/h2\u003e\u003cp\u003eField excitatory postsynaptic potential (fEPSPs) were recorded in the primary motor cortex layer 1/2 using glass electrodes filled with ACSF. Synaptic responses were elicited by applying single electric stimulation to layer \u0026frac12; through a stimulating electrode (concentric bipolar microelectrode, FHC, USA), and field potentials were recorded in the same layer. The signals were amplified (MultiClamp 700B) and digitized (Digidata 1550B, Molecular Devices). After 20 minutes of stable baseline recording, pp-LFS and sp-LFS protocols were applied. The fEPSP amplitudes were normalized to baseline, monitored for 1 h, and averaged over the last 5 minutes.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003ePatch-clamp recording\u003c/h2\u003e\u003cp\u003eWhole-cell recordings of superficial layer (L2/3) pyramidal neurons in the motor cortex were performed. Patch pipettes (3\u0026ndash;7 MΩ) were filled with an internal solution containing 135 mM K-gluconate, 7 mM NaCl, 10 mM HEPES, 0.2 mM EGTA, 4 mM Na\u003csub\u003e2\u003c/sub\u003e-ATP, and 0.2 mM Na-GTP (pH 7.3\u0026ndash;7.4 adjusted with KOH; 292\u0026ndash;293 mOsm adjusted with sucrose). RMP was measured 3 minutes after break-in. Intrinsic excitability was assessed in current-clamp mode by biasing the membrane potential to -70 mV via steady current injection and delivering step currents from \u0026minus;\u0026thinsp;400 to +\u0026thinsp;800 pA in 100-pA increments. R\u003csub\u003ein\u003c/sub\u003e was determined from the voltage responses to a -100 pA current injection. The AP properties were quantified using the first spike elicited by the minimal suprathreshold-depolarizing current injection. The AP threshold was defined as the membrane potential at which the first derivative of voltage over time (dV/dt) exceeded 20 mV/ms. The AP amplitude was calculated as the voltage difference between the AP threshold and peak AP. The AP half-width was calculated as 50% of the amplitude, which was defined as the duration between the rising and falling phases at half-maximal height. The maximum rise and decay rates were determined from the peak positive and negative dV/dt values, respectively. The AHP amplitude was measured as the difference between the threshold voltage and the most negative membrane potential reached after the AP. sEPSCs were recorded in voltage-clamp mode at a -70 mV holding potential for 3 minutes. The data were acquired with a MultiClamp 700B amplifier, digitized using a Digidata 1550B, and analyzed offline using pCLAMP software (Molecular Devices).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eStatistics\u003c/h2\u003e\u003cp\u003eAll statistical analyses were performed using SPSS 28.0 (IBM Corp., Armonk, NY, USA). All graphs were generated using GraphPad Prism 8 (GraphPad Software Inc., La Jolla, CA, USA), and final the arrangements and labeling were completed using Adobe Illustrator CC 2019 (Adobe Inc., San Jose, CA, USA). Axon pCLAMP11 Electrophysiology Data Acquisition and Analysis Software (Molecular Devices, San Jose, CA) was used to numerically present the extracellular field recording data. Data are presented as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard errors of the mean (SEMs) and it is mentioned if normalized for comparison.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eS.C.Y and S.G.Y. conceptualized and designed the study; H.S, T.K, H.H and Y.T.K performed animal behavioral tests and electrophysiology recordings; H.S and Y.J.K performed data analysis; H.S, Y.J.K, J.G.K, Q.Z, S.C.Y and S.G.Y, wrote the paper; Y.J.K, Y.M.H, J.G.K, Q.Z, S.G.Y, and S.C.Y. revised the paper; S.G.Y. and S.C.Y acquired funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing financial interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Innovation and Technology Commission funding of Hong Kong (PRP/050/23FX) for Sungchil Yang and by Incheon National University (International Cooperative) for Sunggu Yang.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePietracupa, S. et al. Understanding the role of cerebellum in early Parkinson's disease: a structural and functional MRI study. \u003cem\u003eNPJ Parkinsons Dis.\u003c/em\u003e \u003cb\u003e10\u003c/b\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41531-024-00727-w\u003c/span\u003e\u003cspan address=\"10.1038/s41531-024-00727-w\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCagle, J. N. et al. Chronic intracranial recordings in the globus pallidus reveal circadian rhythms in Parkinson's disease. \u003cem\u003eNat. Commun.\u003c/em\u003e \u003cb\u003e15\u003c/b\u003e, 4602. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41467-024-48732-0\u003c/span\u003e\u003cspan address=\"10.1038/s41467-024-48732-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTansey, M. G. et al. Inflammation and immune dysfunction in Parkinson disease. \u003cem\u003eNat. Rev. Immunol.\u003c/em\u003e \u003cb\u003e22\u003c/b\u003e, 657\u0026ndash;673. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41577-022-00684-6\u003c/span\u003e\u003cspan address=\"10.1038/s41577-022-00684-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcGregor, M. M. \u0026amp; Nelson, A. B. Circuit mechanisms of Parkinson's disease. \u003cem\u003eNeuron\u003c/em\u003e \u003cb\u003e101\u003c/b\u003e, 1042\u0026ndash;1056. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neuron.2019.03.004\u003c/span\u003e\u003cspan address=\"10.1016/j.neuron.2019.03.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRahimpour, S., Rajkumar, S. \u0026amp; Hallett, M. The Supplementary Motor Complex in Parkinson's Disease. \u003cem\u003eJ. Mov. Disord\u003c/em\u003e. \u003cb\u003e15\u003c/b\u003e, 21\u0026ndash;32. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.14802/jmd.21075\u003c/span\u003e\u003cspan address=\"10.14802/jmd.21075\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRodriguez-Sabate, C., Rodriguez, M. \u0026amp; Morales, I. Studying the functional connectivity of the primary motor cortex with the binarized cross recurrence plot: The influence of Parkinson's disease. \u003cem\u003ePLoS One\u003c/em\u003e. \u003cb\u003e16\u003c/b\u003e, e0252565. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pone.0252565\u003c/span\u003e\u003cspan address=\"10.1371/journal.pone.0252565\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGuo, L. et al. Dynamic rewiring of neural circuits in the motor cortex in mouse models of Parkinson's disease. \u003cem\u003eNat. Neurosci.\u003c/em\u003e \u003cb\u003e18\u003c/b\u003e, 1299\u0026ndash;1309. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/nn.4082\u003c/span\u003e\u003cspan address=\"10.1038/nn.4082\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2015).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDuty, S. Therapeutic potential of targeting group III metabotropic glutamate receptors in the treatment of Parkinson's disease. \u003cem\u003eBr. J. Pharmacol.\u003c/em\u003e \u003cb\u003e161\u003c/b\u003e, 271\u0026ndash;287. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1476-5381.2010.00882.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1476-5381.2010.00882.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2010).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuang, S., Wu, S. J., Sansone, G., Ibrahim, L. A. \u0026amp; Fishell, G. Layer 1 neocortex: Gating and integrating multidimensional signals. \u003cem\u003eNeuron\u003c/em\u003e \u003cb\u003e112\u003c/b\u003e, 184\u0026ndash;200. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neuron.2023.09.041\u003c/span\u003e\u003cspan address=\"10.1016/j.neuron.2023.09.041\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePak, S. et al. Cortical surface plasticity promotes map remodeling and alleviates tinnitus in adult mice. \u003cem\u003eProg Neurobiol.\u003c/em\u003e \u003cb\u003e231\u003c/b\u003e, 102543. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.pneurobio.2023.102543\u003c/span\u003e\u003cspan address=\"10.1016/j.pneurobio.2023.102543\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchuman, B., Dellal, S., Pronneke, A., Machold, R. \u0026amp; Rudy, B. Neocortical Layer 1: An Elegant Solution to Top-Down and Bottom-Up Integration. \u003cem\u003eAnnu. Rev. Neurosci.\u003c/em\u003e \u003cb\u003e44\u003c/b\u003e, 221\u0026ndash;252. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1146/annurev-neuro-100520-012117\u003c/span\u003e\u003cspan address=\"10.1146/annurev-neuro-100520-012117\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbs, E. et al. Learning-Related Plasticity in Dendrite-Targeting Layer 1 Interneurons. \u003cem\u003eNeuron\u003c/em\u003e 100, 684\u0026ndash;699 e686, (2018). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neuron.2018.09.001\u003c/span\u003e\u003cspan address=\"10.1016/j.neuron.2018.09.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIbrahim, L. A. et al. Cross-Modality Sharpening of Visual Cortical Processing through Layer-1-Mediated Inhibition and Disinhibition. \u003cem\u003eNeuron\u003c/em\u003e \u003cb\u003e89\u003c/b\u003e, 1031\u0026ndash;1045. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neuron.2016.01.027\u003c/span\u003e\u003cspan address=\"10.1016/j.neuron.2016.01.027\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2016).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLetzkus, J. J. et al. A disinhibitory microcircuit for associative fear learning in the auditory cortex. \u003cem\u003eNature\u003c/em\u003e \u003cb\u003e480\u003c/b\u003e, 331\u0026ndash;335. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/nature10674\u003c/span\u003e\u003cspan address=\"10.1038/nature10674\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2011).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHosp, J. A., Molina-Luna, K., Hertler, B., Atiemo, C. O. \u0026amp; Luft, A. R. Dopaminergic modulation of motor maps in rat motor cortex: an in vivo study. \u003cem\u003eNeuroscience\u003c/em\u003e \u003cb\u003e159\u003c/b\u003e, 692\u0026ndash;700. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neuroscience.2008.12.056\u003c/span\u003e\u003cspan address=\"10.1016/j.neuroscience.2008.12.056\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2009).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJacobs, K. M. \u0026amp; Donoghue, J. P. Reshaping the cortical motor map by unmasking latent intracortical connections. \u003cem\u003eScience\u003c/em\u003e \u003cb\u003e251\u003c/b\u003e, 944\u0026ndash;947. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1126/science.2000496\u003c/span\u003e\u003cspan address=\"10.1126/science.2000496\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (1991).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUeki, Y. et al. Altered plasticity of the human motor cortex in Parkinson's disease. \u003cem\u003eAnn. Neurol.\u003c/em\u003e \u003cb\u003e59\u003c/b\u003e, 60\u0026ndash;71. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/ana.20692\u003c/span\u003e\u003cspan address=\"10.1002/ana.20692\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2006).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKishore, A., Joseph, T., Velayudhan, B., Popa, T. \u0026amp; Meunier, S. Early, severe and bilateral loss of LTP and LTD-like plasticity in motor cortex (M1) in de novo Parkinson's disease. \u003cem\u003eClin. Neurophysiol.\u003c/em\u003e \u003cb\u003e123\u003c/b\u003e, 822\u0026ndash;828. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.clinph.2011.06.034\u003c/span\u003e\u003cspan address=\"10.1016/j.clinph.2011.06.034\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2012).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKwan, C. et al. Metabotropic glutamate receptors in Parkinson's disease. \u003cem\u003eInt. Rev. Neurobiol.\u003c/em\u003e \u003cb\u003e168\u003c/b\u003e, 1\u0026ndash;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/bs.irn.2022.10.001\u003c/span\u003e\u003cspan address=\"10.1016/bs.irn.2022.10.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang, Z. et al. Roles of Glutamate Receptors in Parkinson's Disease. \u003cem\u003eInt. J. Mol. Sci.\u003c/em\u003e \u003cb\u003e20\u003c/b\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/ijms20184391\u003c/span\u003e\u003cspan address=\"10.3390/ijms20184391\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eConn, P. J., Battaglia, G., Marino, M. J. \u0026amp; Nicoletti, F. Metabotropic glutamate receptors in the basal ganglia motor circuit. \u003cem\u003eNat. Rev. Neurosci.\u003c/em\u003e \u003cb\u003e6\u003c/b\u003e, 787\u0026ndash;798. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/nrn1763\u003c/span\u003e\u003cspan address=\"10.1038/nrn1763\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2005).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGuimaraes, I. M., Carvalho, T. G., Ferguson, S. S., Pereira, G. S. \u0026amp; Ribeiro, F. M. The metabotropic glutamate receptor 5 role on motor behavior involves specific neural substrates. \u003cem\u003eMol. Brain\u003c/em\u003e. \u003cb\u003e8\u003c/b\u003e, 24. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13041-015-0113-2\u003c/span\u003e\u003cspan address=\"10.1186/s13041-015-0113-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2015).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTarhan, L. et al. Single Cell Portal: an interactive home for single-cell genomics data. \u003cem\u003ebioRxiv\u003c/em\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1101/2023.07.13.548886\u003c/span\u003e\u003cspan address=\"10.1101/2023.07.13.548886\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSiletti, K. et al. Transcriptomic diversity of cell types across the adult human brain. \u003cem\u003eScience\u003c/em\u003e \u003cb\u003e382\u003c/b\u003e, eadd7046. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1126/science.add7046\u003c/span\u003e\u003cspan address=\"10.1126/science.add7046\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTasic, B. et al. Shared and distinct transcriptomic cell types across neocortical areas. \u003cem\u003eNature\u003c/em\u003e \u003cb\u003e563\u003c/b\u003e, 72\u0026ndash;78. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41586-018-0654-5\u003c/span\u003e\u003cspan address=\"10.1038/s41586-018-0654-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang, Y. et al. Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse. \u003cem\u003eNeuron\u003c/em\u003e \u003cb\u003e89\u003c/b\u003e, 37\u0026ndash;53. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neuron.2015.11.013\u003c/span\u003e\u003cspan address=\"10.1016/j.neuron.2015.11.013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2016).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShcherbatyy, V. et al. A digital atlas of ion channel expression patterns in the two-week-old rat brain. \u003cem\u003eNeuroinformatics\u003c/em\u003e \u003cb\u003e13\u003c/b\u003e, 111\u0026ndash;125. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12021-014-9247-0\u003c/span\u003e\u003cspan address=\"10.1007/s12021-014-9247-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2015).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLein, E. S. et al. Genome-wide atlas of gene expression in the adult mouse brain. \u003cem\u003eNature\u003c/em\u003e \u003cb\u003e445\u003c/b\u003e, 168\u0026ndash;176. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/nature05453\u003c/span\u003e\u003cspan address=\"10.1038/nature05453\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2007).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShin, H. et al. A Wireless Cortical Surface Implant for Diagnosing and Alleviating Parkinson's Disease Symptoms in Freely Moving Animals. \u003cem\u003eAdv. Healthc. Mater.\u003c/em\u003e \u003cb\u003e14\u003c/b\u003e, e2405179. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/adhm.202405179\u003c/span\u003e\u003cspan address=\"10.1002/adhm.202405179\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNam, J. et al. Cortical Stimulation-Based Transcriptome Shifts on Parkinson's Disease Animal Model. \u003cem\u003eASN Neuro\u003c/em\u003e. \u003cb\u003e17\u003c/b\u003e, 2513881. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/17590914.2025.2513881\u003c/span\u003e\u003cspan address=\"10.1080/17590914.2025.2513881\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKang, S. J. \u0026amp; Kaang, B. K. Metabotropic glutamate receptor dependent long-term depression in the cortex. \u003cem\u003eKorean J. Physiol. Pharmacol.\u003c/em\u003e \u003cb\u003e20\u003c/b\u003e, 557\u0026ndash;564. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4196/kjpp.2016.20.6.557\u003c/span\u003e\u003cspan address=\"10.4196/kjpp.2016.20.6.557\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2016).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYang, S. et al. Integrity of mGluR-LTD in the associative/commissural inputs to CA3 correlates with successful aging in rats. \u003cem\u003eJ. Neurosci.\u003c/em\u003e \u003cb\u003e33\u003c/b\u003e, 12670\u0026ndash;12678. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1523/JNEUROSCI.1086-13.2013\u003c/span\u003e\u003cspan address=\"10.1523/JNEUROSCI.1086-13.2013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2013).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKemp, N. \u0026amp; Bashir, Z. I. Long-term depression: a cascade of induction and expression mechanisms. \u003cem\u003eProg Neurobiol.\u003c/em\u003e \u003cb\u003e65\u003c/b\u003e, 339\u0026ndash;365. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s0301-0082(01)00013-2\u003c/span\u003e\u003cspan address=\"10.1016/s0301-0082(01)00013-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2001).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuber, K. M., Kayser, M. S. \u0026amp; Bear, M. F. Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. \u003cem\u003eScience\u003c/em\u003e \u003cb\u003e288\u003c/b\u003e, 1254\u0026ndash;1257. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1126/science.288.5469.1254\u003c/span\u003e\u003cspan address=\"10.1126/science.288.5469.1254\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2000).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKemp, N. \u0026amp; Bashir, Z. I. Induction of LTD in the adult hippocampus by the synaptic activation of AMPA/kainate and metabotropic glutamate receptors. \u003cem\u003eNeuropharmacology\u003c/em\u003e \u003cb\u003e38\u003c/b\u003e, 495\u0026ndash;504. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s0028-3908(98)00222-6\u003c/span\u003e\u003cspan address=\"10.1016/s0028-3908(98)00222-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (1999).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShin, H. et al. A wireless cortical surface implant for diagnosing and alleviating Parkinson's disease symptoms in freely moving animals. \u003cem\u003eAdv. Healthc. Mater.\u003c/em\u003e \u003cb\u003ee2405179\u003c/b\u003e \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/adhm.202405179\u003c/span\u003e\u003cspan address=\"10.1002/adhm.202405179\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCannon, W. B. \u0026amp; Rosenblueth, A. \u003cem\u003eThe supersensitivity of denervated structures; a law of denervation\u003c/em\u003e (Macmillan Co., 1949).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLuscher, C. \u0026amp; Huber, K. M. Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. \u003cem\u003eNeuron\u003c/em\u003e \u003cb\u003e65\u003c/b\u003e, 445\u0026ndash;459. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neuron.2010.01.016\u003c/span\u003e\u003cspan address=\"10.1016/j.neuron.2010.01.016\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2010).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMozafari, R., Karimi-Haghighi, S., Fattahi, M., Kalivas, P. \u0026amp; Haghparast, A. A review on the role of metabotropic glutamate receptors in neuroplasticity following psychostimulant use disorder. \u003cem\u003eProg Neuropsychopharmacol. Biol. Psychiatry\u003c/em\u003e. \u003cb\u003e124\u003c/b\u003e, 110735. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.pnpbp.2023.110735\u003c/span\u003e\u003cspan address=\"10.1016/j.pnpbp.2023.110735\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMadadi Asl, M., Vahabie, A. H. \u0026amp; Valizadeh, A. Dopaminergic Modulation of Synaptic Plasticity, Its Role in Neuropsychiatric Disorders, and Its Computational Modeling. \u003cem\u003eBasic. Clin. Neurosci.\u003c/em\u003e \u003cb\u003e10\u003c/b\u003e, 1\u0026ndash;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.32598/bcn.9.10.125\u003c/span\u003e\u003cspan address=\"10.32598/bcn.9.10.125\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbd-Elrahman, K. S., Sarasija, S. \u0026amp; Ferguson, S. S. G. The Role of Neuroglial Metabotropic Glutamate Receptors in Alzheimer's Disease. \u003cem\u003eCurr. Neuropharmacol.\u003c/em\u003e \u003cb\u003e21\u003c/b\u003e, 273\u0026ndash;283. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2174/1570159X19666210916102638\u003c/span\u003e\u003cspan address=\"10.2174/1570159X19666210916102638\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSu, L. D., Wang, N., Han, J. \u0026amp; Shen, Y. Group 1 Metabotropic Glutamate Receptors in Neurological and Psychiatric Diseases: Mechanisms and Prospective. \u003cem\u003eNeuroscientist\u003c/em\u003e \u003cb\u003e28\u003c/b\u003e, 453\u0026ndash;468. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/10738584211021018\u003c/span\u003e\u003cspan address=\"10.1177/10738584211021018\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi, S. H., Colson, T. L., Abd-Elrahman, K. S. \u0026amp; Ferguson, S. S. G. Metabotropic Glutamate Receptor 5 Antagonism Reduces Pathology and Differentially Improves Symptoms in Male and Female Heterozygous zQ175 Huntington's Mice. \u003cem\u003eFront. Mol. Neurosci.\u003c/em\u003e \u003cb\u003e15\u003c/b\u003e, 801757. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fnmol.2022.801757\u003c/span\u003e\u003cspan address=\"10.3389/fnmol.2022.801757\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBertoglio, D. et al. Elevated Type 1 Metabotropic Glutamate Receptor Availability in a Mouse Model of Huntington's Disease: a Longitudinal PET Study. \u003cem\u003eMol. Neurobiol.\u003c/em\u003e \u003cb\u003e57\u003c/b\u003e, 2038\u0026ndash;2047. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12035-019-01866-5\u003c/span\u003e\u003cspan address=\"10.1007/s12035-019-01866-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRibeiro, F. M., Vieira, L. B., Pires, R. G., Olmo, R. P. \u0026amp; Ferguson, S. S. Metabotropic glutamate receptors and neurodegenerative diseases. \u003cem\u003ePharmacol. Res.\u003c/em\u003e \u003cb\u003e115\u003c/b\u003e, 179\u0026ndash;191. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.phrs.2016.11.013\u003c/span\u003e\u003cspan address=\"10.1016/j.phrs.2016.11.013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2017).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRibeiro, F. M. et al. Metabotropic glutamate receptor 5 as a potential therapeutic target in Huntington's disease. \u003cem\u003eExpert Opin. Ther. Tar\u003c/em\u003e. \u003cb\u003e18\u003c/b\u003e, 1293\u0026ndash;1304. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1517/14728222.2014.948419\u003c/span\u003e\u003cspan address=\"10.1517/14728222.2014.948419\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2014).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRibeiro, F. M. et al. Metabotropic Glutamate Receptor-Mediated Cell Signaling Pathways Are Altered in a Mouse Model of Huntington's Disease. \u003cem\u003eJ. Neurosci.\u003c/em\u003e \u003cb\u003e30\u003c/b\u003e, 316\u0026ndash;324. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1523/Jneurosci.4974-09.2010\u003c/span\u003e\u003cspan address=\"10.1523/Jneurosci.4974-09.2010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2010).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGubellini, P., Centonze, D., Tropepi, D., Bernardi, G. \u0026amp; Calabresi, P. Induction of corticostriatal LTP by 3-nitropropionic acid requires the activation of mGluR1/PKC pathway. \u003cem\u003eNeuropharmacology\u003c/em\u003e \u003cb\u003e46\u003c/b\u003e, 761\u0026ndash;769. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neuropharm.2003.11.021\u003c/span\u003e\u003cspan address=\"10.1016/j.neuropharm.2003.11.021\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2004).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRammes, G., Hasenjager, A., Sroka-Saidi, K., Deussing, J. M. \u0026amp; Parsons, C. G. Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 metabotropic glutamate receptors in mediating the synaptotoxic effects of beta-amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices. \u003cem\u003eNeuropharmacology\u003c/em\u003e \u003cb\u003e60\u003c/b\u003e, 982\u0026ndash;990. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neuropharm.2011.01.051\u003c/span\u003e\u003cspan address=\"10.1016/j.neuropharm.2011.01.051\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2011).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNg, A. N., Salter, E. W., Georgiou, J., Bortolotto, Z. A. \u0026amp; Collingridge, G. L. Amyloid-beta(1\u0026ndash;42) oligomers enhance mGlu(5)R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling. \u003cem\u003eiScience\u003c/em\u003e 26, 108412, (2023). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.isci.2023.108412\u003c/span\u003e\u003cspan address=\"10.1016/j.isci.2023.108412\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi, S. et al. Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. \u003cem\u003eNeuron\u003c/em\u003e \u003cb\u003e62\u003c/b\u003e, 788\u0026ndash;801. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neuron.2009.05.012\u003c/span\u003e\u003cspan address=\"10.1016/j.neuron.2009.05.012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2009).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHsieh, H. et al. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. \u003cem\u003eNeuron\u003c/em\u003e \u003cb\u003e52\u003c/b\u003e, 831\u0026ndash;843. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neuron.2006.10.035\u003c/span\u003e\u003cspan address=\"10.1016/j.neuron.2006.10.035\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2006).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJiang, X., Lin, W., Cheng, Y. \u0026amp; Wang, D. mGluR5 facilitates long-term synaptic depression in a stress-induced depressive mouse model. \u003cem\u003eCan. J. Psychiatry\u003c/em\u003e. \u003cb\u003e65\u003c/b\u003e, 347\u0026ndash;355. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/0706743719874162\u003c/span\u003e\u003cspan address=\"10.1177/0706743719874162\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi, M. X. et al. Increased Homer1-mGluR5 mediates chronic stress-induced depressive-like behaviors and glutamatergic dysregulation via activation of PERK-eIF2alpha. \u003cem\u003eProg Neuropsychopharmacol. Biol. Psychiatry\u003c/em\u003e. \u003cb\u003e95\u003c/b\u003e, 109682. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.pnpbp.2019.109682\u003c/span\u003e\u003cspan address=\"10.1016/j.pnpbp.2019.109682\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePignatelli, M. et al. Enhanced mGlu5-receptor dependent long-term depression at the Schaffer collateral-CA1 synapse of congenitally learned helpless rats. \u003cem\u003eNeuropharmacology\u003c/em\u003e \u003cb\u003e66\u003c/b\u003e, 339\u0026ndash;347. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neuropharm.2012.05.046\u003c/span\u003e\u003cspan address=\"10.1016/j.neuropharm.2012.05.046\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2013).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePostnikova, T. Y. et al. Transient switching of NMDA-dependent long-term synaptic potentiation in CA3-CA1 hippocampal synapses to mGluR(1)-dependent potentiation after pentylenetetrazole-induced acute seizures in young rats. \u003cem\u003eCell. Mol. Neurobiol.\u003c/em\u003e \u003cb\u003e39\u003c/b\u003e, 287\u0026ndash;300. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10571-018-00647-3\u003c/span\u003e\u003cspan address=\"10.1007/s10571-018-00647-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBernard, P. B., Castano, A. M., Bayer, K. U. \u0026amp; Benke, T. A. Necessary, but not sufficient: insights into the mechanisms of mGluR mediated long-term depression from a rat model of early life seizures. \u003cem\u003eNeuropharmacology\u003c/em\u003e \u003cb\u003e84\u003c/b\u003e, 1\u0026ndash;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neuropharm.2014.04.011\u003c/span\u003e\u003cspan address=\"10.1016/j.neuropharm.2014.04.011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2014).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKirschstein, T. et al. Loss of metabotropic glutamate receptor-dependent long-term depression via downregulation of mGluR5 after status epilepticus. \u003cem\u003eJ. Neurosci.\u003c/em\u003e \u003cb\u003e27\u003c/b\u003e, 7696\u0026ndash;7704. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1523/JNEUROSCI.4572-06.2007\u003c/span\u003e\u003cspan address=\"10.1523/JNEUROSCI.4572-06.2007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2007).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuber, K. M., Gallagher, S. M., Warren, S. T. \u0026amp; Bear, M. F. Altered synaptic plasticity in a mouse model of fragile X mental retardation. \u003cem\u003eProc. Natl. Acad. Sci. U S A\u003c/em\u003e. \u003cb\u003e99\u003c/b\u003e, 7746\u0026ndash;7750. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1073/pnas.122205699\u003c/span\u003e\u003cspan address=\"10.1073/pnas.122205699\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2002).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNosyreva, E. D. \u0026amp; Huber, K. M. Metabotropic receptor-dependent long-term depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. \u003cem\u003eJ. Neurophysiol.\u003c/em\u003e \u003cb\u003e95\u003c/b\u003e, 3291\u0026ndash;3295. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1152/jn.01316.2005\u003c/span\u003e\u003cspan address=\"10.1152/jn.01316.2005\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2006).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHou, L. et al. Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression. \u003cem\u003eNeuron\u003c/em\u003e \u003cb\u003e51\u003c/b\u003e, 441\u0026ndash;454. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neuron.2006.07.005\u003c/span\u003e\u003cspan address=\"10.1016/j.neuron.2006.07.005\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2006).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMichalon, A. et al. Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. \u003cem\u003eNeuron\u003c/em\u003e \u003cb\u003e74\u003c/b\u003e, 49\u0026ndash;56. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.neuron.2012.03.009\u003c/span\u003e\u003cspan address=\"10.1016/j.neuron.2012.03.009\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2012).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAuerbach, B. D. \u0026amp; Bear, M. F. Loss of the fragile X mental retardation protein decouples metabotropic glutamate receptor dependent priming of long-term potentiation from protein synthesis. \u003cem\u003eJ. Neurophysiol.\u003c/em\u003e \u003cb\u003e104\u003c/b\u003e, 1047\u0026ndash;1051. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1152/jn.00449.2010\u003c/span\u003e\u003cspan address=\"10.1152/jn.00449.2010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2010).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKang, S. J. et al. Plasticity of metabotropic glutamate receptor-dependent long-term depression in the anterior cingulate cortex after amputation. \u003cem\u003eJ. Neurosci.\u003c/em\u003e \u003cb\u003e32\u003c/b\u003e, 11318\u0026ndash;11329. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1523/JNEUROSCI.0146-12.2012\u003c/span\u003e\u003cspan address=\"10.1523/JNEUROSCI.0146-12.2012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2012).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Parkinson’s disease, Sensorimotor cortex, Motor cortex, Long-term synaptic plasticity, Metabotropic glutamate receptor","lastPublishedDoi":"10.21203/rs.3.rs-7634193/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7634193/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eParkinson\u0026rsquo;s disease (PD), a neurodegenerative disorder, is caused by dopaminergic lesions in the substantia nigra pars compacta that lead to motor deficits. Although metabotropic glutamate receptors (mGluRs) are key regulators of synaptic plasticity, their contribution to cortical surface long-term depression (LTD) in PD remains unknown. We used the 6-hydroxydopamine (6-OHDA) rat model of PD to examine synaptic plasticity in the primary motor cortex (M1) surface. Extracellular field recordings revealed that mGluR-dependent LTD induced by paired-pulse low-frequency stimulation (pp-LFS) was markedly reduced in PD rats, whereas N-methyl-D-aspartate receptor (NMDAR)-dependent LTD remained unchanged. Whole-cell patch-clamp recordings showed altered action potential (AP) kinetics, such as narrower spike half-widths and faster repolarization, in PD neurons on the M1 surface, suggesting that reduced LTD and sharper AP kinetics contribute to motor deficits. Combined with previous evidence of enhanced mGluR\u003csub\u003e1/5\u003c/sub\u003e-dependent long-term potentiation (LTP) in PD, these results indicate the involvement of a selective disruption of mGluR-mediated plasticity in maladaptive plasticity and motor dysfunction. Our study highlights group I mGluRs as both key modulators of sensorimotor homeostasis and potential therapeutic targets for restoring the synaptic balance following alteration by sensorimotor deficits.\u003c/p\u003e","manuscriptTitle":"Altered mGluR1/5-driven plasticity in the motor cortical surface as a biomarker for Parkinson’s disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-16 14:26:29","doi":"10.21203/rs.3.rs-7634193/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"426ef004-54ec-40cb-8a62-cd63d1c3034e","owner":[],"postedDate":"October 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":56418874,"name":"Health sciences/Neurology"},{"id":56418875,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2025-11-03T01:23:31+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-16 14:26:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7634193","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7634193","identity":"rs-7634193","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}