Type-1 metabotropic glutamate receptor signaling in cerebellar Purkinje cells in health and disease

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Purkinje cells are the sole output neurons from the cerebellar cortex and therefore play crucial roles in the overall function of the cerebellum. The type-1 metabotropic glutamate receptor (mGluR1) is a key “hub” molecule that is critically involved in the regulation of synaptic wiring, excitability, synaptic response, and synaptic plasticity of Purkinje cells. In this review, we aim to highlight how mGluR1 controls these events in Purkinje cells. We also describe emerging evidence that altered mGluR1 signaling in Purkinje cells underlies cerebellar dysfunctions in several clinically relevant mouse models of human ataxias." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/6-416", "name": "Type-1 metabotropic glutamate receptor signaling in cerebellar Purkinje..." } } ] } Home Browse Type-1 metabotropic glutamate receptor signaling in cerebellar Purkinje... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Kano M and Watanabe T. Type-1 metabotropic glutamate receptor signaling in cerebellar Purkinje cells in health and disease [version 1; peer review: 3 approved] . F1000Research 2017, 6 (F1000 Faculty Rev):416 ( https://doi.org/10.12688/f1000research.10485.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Review Type-1 metabotropic glutamate receptor signaling in cerebellar Purkinje cells in health and disease [version 1; peer review: 3 approved] Masanobu Kano https://orcid.org/0000-0002-0725-3292 1 , Takaki Watanabe https://orcid.org/0000-0001-8746-1683 1 Masanobu Kano https://orcid.org/0000-0002-0725-3292 1 , Takaki Watanabe https://orcid.org/0000-0001-8746-1683 1 PUBLISHED 04 Apr 2017 Author details Author details 1 Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract The cerebellum is a brain structure involved in coordination, control, and learning of movements, as well as certain aspects of cognitive function. Purkinje cells are the sole output neurons from the cerebellar cortex and therefore play crucial roles in the overall function of the cerebellum. The type-1 metabotropic glutamate receptor (mGluR1) is a key “hub” molecule that is critically involved in the regulation of synaptic wiring, excitability, synaptic response, and synaptic plasticity of Purkinje cells. In this review, we aim to highlight how mGluR1 controls these events in Purkinje cells. We also describe emerging evidence that altered mGluR1 signaling in Purkinje cells underlies cerebellar dysfunctions in several clinically relevant mouse models of human ataxias. READ ALL READ LESS Keywords Purkinje cell, signaling, metabotropic glutamate receptor, cerebellum, cognitive function Corresponding Author(s) Masanobu Kano ( [email protected] ) Close Corresponding author: Masanobu Kano Competing interests: The authors declare that they have no competing interests. Grant information: This work was supported by the Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (grant 25000015), and the Brain/MINDS grant from the Japan Agency for Medical Research and Development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2017 Kano M and Watanabe T. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication). How to cite: Kano M and Watanabe T. Type-1 metabotropic glutamate receptor signaling in cerebellar Purkinje cells in health and disease [version 1; peer review: 3 approved] . F1000Research 2017, 6 (F1000 Faculty Rev):416 ( https://doi.org/10.12688/f1000research.10485.1 ) First published: 04 Apr 2017, 6 (F1000 Faculty Rev):416 ( https://doi.org/10.12688/f1000research.10485.1 ) Latest published: 04 Apr 2017, 6 (F1000 Faculty Rev):416 ( https://doi.org/10.12688/f1000research.10485.1 ) Introduction The cerebellum is involved in coordination, control, and learning of movements and also in some aspects of cognitive functions 1 , 2 . Purkinje cells are the sole output neurons from the cerebellar cortex and receive two distinct excitatory inputs, namely parallel fibers and climbing fibers 1 , 3 , 4 ( Figure 1 ). Parallel fibers are the axons of granule cells in the cerebellar cortex and form synapses on spines of Purkinje cell dendrites. Synaptic inputs from individual parallel fibers are weak, but numerous (as many as 100,000 in mice) parallel fibers innervate each Purkinje cell. Granule cells are driven by excitatory inputs from mossy fibers originating from various precerebellar nuclei and the spinal cord ( Figure 1 ). Mossy fibers are thought to convey sensory information arising from various body parts and motor command signals from the upper centers through mossy fibers ( Figure 1 ). Climbing fibers originate from the inferior olive in the contralateral medulla oblongata and form direct synaptic contacts with Purkinje cells ( Figure 1 ). A single Purkinje cell is innervated by only one climbing fiber in the adult cerebellum, but each climbing fiber makes hundreds of strong connections with Purkinje cell proximal dendrites ( Figure 1 ). Purkinje cells then form inhibitory synaptic connections on neurons in the deep cerebellar nuclei and vestibular nuclei ( Figure 1 ). Climbing fibers are thought to convey error signals that represent the mismatch between the motor command and the actual movement 1 , 5 ( Figure 1 ). A predominant theory of cerebellar motor learning is based on long-term depression (LTD) that occurs at parallel fiber–Purkinje cell synapses when they are activated conjunctively with climbing fiber input for a certain period of time 1 , 5 , 6 . Parallel fiber inputs associated with movement error will be depressed by LTD, and information flow through the cerebellar circuitry changes so as to support and facilitate the correct movements 1 , 5 , 6 ( Figure 1 ). Synaptic connections onto Purkinje cells from climbing fiber and parallel fibers as well as from inhibitory interneurons are formed and established during postnatal development 7 – 14 . Therefore, activity and synaptic responses of Purkinje cells, LTD at parallel fiber–Purkinje cell synapses, and establishment of synaptic wiring onto Purkinje cells during postnatal development are crucial factors for proper functions of the cerebellum. Figure 1. Simplified scheme of cerebellar neural circuitry. The metabotropic glutamate receptor (mGluR) family of G-protein-coupled receptors (GPCRs) consists of eight members, mGluR1 to mGluR8, which are divided into group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3), and group III (mGluR4, mGluR6, mGluR7, and mGluR8) 15 , 16 . Group I mGluRs are coupled to the G-protein G q family (G q and G 11 ), which mediates inositol trisphosphate (IP 3 )-induced Ca 2+ mobilization and activation of protein kinase C (PKC). Purkinje cells in the cerebellum strongly express mGluR1 17 – 20 , and many studies have shown that mGluR1 signaling is essential for various aspects of cerebellar function 21 – 24 . A crucial role for mGluR1 in Purkinje cells is best illustrated by the multiple phenotypes of cerebellar dysfunction in mGluR1-knockout mice 25 – 27 , which can be rescued by Purkinje cell-specific re-expression of mGluR1 28 , 29 . Moreover, dysregulation of mGluR1 signaling in Purkinje cells has been found in several clinically relevant mouse models of human cerebellar ataxias, and mutations of mGluR1 and related molecules have been reported in certain types of human ataxias 24 , 30 . Thus, this review aims to summarize the roles of Purkinje cell mGluR1 signaling in normal cerebellar functions and their dysfunctions relevant to human ataxias. Background Among a number of signaling molecules that have been identified to be involved in cerebellar LTD, mGluR1 and its downstream molecules constitute a canonical pathway for LTD (see Figure 2 ). Mutant mice lacking mGluR1 or its downstream molecules show deficient LTD, clear impairment of cerebellum-dependent motor learning, and motor discoordination 25 , 26 , supporting the notion that cerebellar LTD is a cellular basis of motor learning 1 , 5 , 31 . It has also been shown that the mGluR1 signaling cascade is crucial for the elimination of redundant climbing fiber to Purkinje cell connections during postnatal cerebellar development 27 , 32 (see Figure 3 ). This phenomenon is known to be a representative model of “synapse elimination” or “axon pruning” in the developing brain 7 , 8 , 33 – 36 . In mutant mice lacking mGluR1 or its downstream molecules (Gαq, phospholipase Cβ4, or PKCγ), multiple climbing fiber innervation of Purkinje cells persists into adulthood because of the impairment of climbing fiber elimination during the third postnatal week 27 , 32 , 37 – 39 ( Figure 3 ). Importantly, deficient LTD, impaired motor learning, motor discoordination, and impaired climbing fiber synapse elimination are all restored by Purkinje cell-specific expression of mGluR1a, a predominant splice variant in Purkinje cells, into global mGluR1-knockout mice 28 . This result clearly indicates that the mGluR1 cascade within Purkinje cells is essential for neural circuit development, synaptic plasticity, and motor learning in the cerebellum 23 , 40 . Figure 2. Schematic diagram of type-1 metabotropic glutamate receptor (mGluR1)-mediated long-term depression (LTD) at parallel fiber to Purkinje cell synapse. The long C-terminal domain of mGluR1a is required for inositol trisphosphate (IP 3 )-mediated Ca 2+ release and LTD induction. mGluR1b lacking this C-terminal domain cannot drive the cascade for LTD induction. A1R, A 1 -subtype adenosine receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; DG, diacylglycerol; CaV3.1, Ca V 3.1 T-type voltage-dependent Ca 2+ channel; GABA B R, type-B γ-aminobutyric acid receptor; PIP 2 , phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; PQ, P/Q-type voltage-dependent Ca 2+ channel. Figure 3. Schematic diagram of type-1 metabotropic glutamate receptor (mGluR1) signaling in Purkinje cells required for developmental synapse elimination. Parallel fiber synaptic inputs activate mGluR1 and its downstream signaling (Gq – phospholipase Cβ4 [PLCβ4] – protein kinase Cγ [PKCγ]) in Purkinje cells. Sema7A retrogradely acts on its Plexin C1 (PlxnC1)/Integrin B1 (ItgB1) receptor on “weak” climbing fibers and eliminates them from the soma during postnatal day (P)15 to P18. The same mGluR1 to PKCγ signaling eliminates parallel fiber synapses from proximal dendrites during P15 to P30. The long C-terminal domain of mGluR1a is required for climbing fiber synapse elimination. GluD2, glutamate receptor δ2. Activation of mGluR1 by repetitive parallel fiber stimulation induces slow excitatory postsynaptic potentials (EPSPs)/excitatory postsynaptic currents (EPSCs) in Purkinje cells 41 – 43 . This slow EPSC has been shown to be mediated by an inward cation current through the TRPC3 channel 44 ( Figure 4 ). Repetitive parallel fiber stimulation also induces mGluR1-mediated production of IP 3 and local Ca 2+ release from internal stores in Purkinje cell dendrites 45 , 46 ( Figure 4 ). Furthermore, the activation of mGluR1 by repetitive parallel fiber stimulation induces the release of an endocannabinoid that acts retrogradely on cannabinoid CB 1 receptors on parallel fibers and climbing fibers and causes transient suppression of glutamate release from parallel fibers and climbing fibers 47 – 50 ( Figure 4 ). The endocannabinoid that mediates retrograde synaptic suppression has been identified as 2-arachidonoylglycerol (2-AG), which is produced by diacylglycerol lipase α 51 , 52 . This retrograde signaling mediated by 2-AG is required for the induction of LTD at parallel fiber synapses 53 , 54 , and CB 1 knockout mice exhibit a clear impairment of delay eyeblink conditioning, a representative of cerebellum-dependent motor learning 55 . Figure 4. Schematic diagram showing type-1 metabotropic glutamate receptor (mGluR1)-mediated Ca 2+ mobilization and interaction between mGluR1 and other G-protein-coupled receptors (GPCRs) or ion channels. The long C-terminal domain of mGluR1a is required for proper perisynaptic localization of mGluR1 and inositol trisphosphate (IP 3 )-mediated Ca 2+ release but is dispensable for short transient receptor potential channel 3 (TRPC3)-mediated inward currents. 2-AG, 2-arachidonoylglycerol; CB1, cannabinoid receptor type-1; DGL, diacylglycerol lipase; EPSC, excitatory postsynaptic current; Kv4.3, Kv4.3 voltage-dependent K + channel; STIM1, stromal interaction molecule 1. Several studies have shown that mGluR1 interacts with another GPCR or ion channel either directly or through G-protein (see Figure 4 ). The mGluR1-mediated responses of Purkinje cells in cerebellar slices are enhanced by the activation of type-B γ-aminobutyric acid receptor (GABA B R) through G i/o protein 56 ( Figure 4 ). In cultured Purkinje cells, GABA B R activation enhances LTD by elevating mGluR1 signaling via phospholipase Cβ activation by the G-protein β/γ subunit released as a consequence of GABA B R activation 57 ( Figure 2 ). Moreover, the activation of GABA B R enhances the mGluR1-mediated responses in cultured Purkinje cells through G i/o protein-independent direct interaction between GABA B R and mGluR1 58 ( Figure 4 ). Interestingly, this GABA B R–mGluR1 interaction does not require GABA but is caused by extracellular Ca 2+ 58 ( Figure 4 ). The dynamic range of mGluR1 is positively controlled by extracellular Ca 2+ such that sensitivity of mGluR1 to its agonist is enhanced at low dose range 59 . This mGluR1 sensitization is absent in Purkinje cells lacking GABA B R, indicating that GABA B R can act as a Ca 2+ -dependent cofactor of mGluR1 signaling in Purkinje cells 58 ( Figure 4 ). In contrast, mGluR1-induced inward current in Purkinje cells has been reported to be continuously depressed by activation of G i/o protein-coupled A 1 -subtype adenosine receptor (A1R) 60 ( Figure 1 ). This inhibitory effect from A1R to mGluR1 was independent of G i/o protein, suggesting a direct interaction between the two receptors. It has been shown that mGluR1-induced mobilization of Ca 2+ leads to activation of outward K + current that slowly hyperpolarizes Purkinje cells 61 , 62 . On the other hand, activation of mGluR1 potentiates Ca V 3.1 T-type Ca 2+ channel currents in Purkinje cell dendritic spines through a G-protein- and tyrosine phosphatase-dependent mechanism 63 ( Figure 4 ). Taken together, these studies clearly indicate that mGluR1 plays multiple and crucial roles in the regulation of synaptic wiring, excitability, synaptic transmission, and synaptic plasticity in Purkinje cells. New insight into the roles of mGluR1 in Purkinje cell function Synaptic plasticity and developmental synapse elimination in Purkinje cells Ohtani et al. reintroduced mGluR1b, a short variant that lacks a long carboxyl-terminal domain, into Purkinje cells of global mGluR1-knockout mice (mGluR1b-rescue mice) 29 . As mentioned above, restoration of mGluR1a, which contains the long carboxyl-terminal domain, rescued all the cerebellar deficits in mGluR1-knockout mice 28 . In contrast, mGluR1b-rescue mice exhibited normal TRPC3-mediated slow EPSC and motor coordination but showed impairments in IP 3 -mediated Ca 2+ release, developmental climbing fiber synapse elimination, LTD at parallel fiber to Purkinje cell synapses, and delayed eyeblink conditioning 29 . Furthermore, in mGluR1b-rescue mice, mGluR1b showed dispersed perisynaptic localization at Purkinje cell spines 29 . This study indicates that the long C-terminal domain of mGluR1a is required for proper perisynaptic localization of mGluR1, IP 3 -mediated Ca 2+ release, developmental climbing fiber synapse elimination, LTD induction, and motor learning ( Figure 2 – Figure 4 ). Chae et al. reported that blockade of TRPC3 channels by a broad-spectrum TRPC antagonist or by a TRPC3 antibody suppressed LTD induction at parallel fiber to Purkinje cell synapses 64 . However, the dissociation between TRPC3-mediated slow EPSC and LTD in mGluR1b-rescue mice suggests that TRPC3-mediated slow EPSC is necessary but not sufficient for LTD induction. As for developmental synapse elimination, Uesaka et al. demonstrated that Sema7A, a membrane-bound class of semaphorin, functions as a retrograde signaling molecule from Purkinje cells to losing climbing fibers at the downstream of mGluR1 65 ( Figure 3 ). When Sema7A was knocked down in Purkinje cells by lentivirus-mediated RNA interference during postnatal development, climbing fiber synapse elimination was impaired from postnatal day 15 (P15). Double knockdown of Sema7A and mGluR1 in Purkinje cells caused impairment of climbing fiber synapse elimination to the same extent as single mGluR1 knockdown. Furthermore, expression of Sema7A was significantly reduced in the cerebellum of mGluR1-knockout mice. Importantly, overexpression of Sema7A in mGluR1-knockdown Purkinje cells restored normal climbing fiber synapse elimination. These data indicate that Sema7A mediates climbing fiber synapse elimination downstream of mGluR1 65 . Ichikawa et al. revealed that massive elimination of parallel fiber synapses occurs from around P15 to P30, which requires mGluR1 signaling in Purkinje cells 66 ( Figure 3 ). Climbing fibers and parallel fibers innervate proximal and distal portions of Purkinje cell dendrites, respectively. In between, there is an intermediate dendritic portion with overlapped innervation by climbing fibers and parallel fibers. Ichikawa et al. showed that climbing fiber and parallel fiber territories expanded with marked enlargement of the regions of overlapping innervation until P15 66 . Then, the territories became segregated from P15 to around P30 by massive elimination of parallel fiber synapses from proximal dendrites 66 . Interestingly, this parallel fiber synapse elimination was absent in mGluR1-knockout mice and also in PKCγ-knockout mice, and the defect of mGluR1-knockout mice was rescued by lentivirus-mediated expression of mGluR1a in mGluR1-deficient Purkinje cells 66 ( Figure 3 ). These findings give a new insight into roles of mGluR1 signaling in Purkinje cell synaptic wiring during postnatal development. mGluR1 signaling is essential for eliminating weaker climbing fiber synapses from the soma to establish mono-climbing fiber innervation and also for eliminating parallel fiber synapses from proximal dendrites to segregate climbing fiber and parallel fiber territories in Purkinje cell dendrites. Interaction of mGluR1 and another GPCR or ion channel Kamikubo et al. explored the physiological relevance of direct interaction between A1R and mGluR1 67 . They first demonstrated that the two GPCRs closely co-localized and formed heteromeric complexes on the cell surfaces by using Förster resonance energy transfer analyses in cultured Purkinje cells 67 ( Figure 4 ). Then they showed evidence that A1R antagonizes the induction of LTD by decreasing the ligand sensitivity of mGluR1 but not the coupling efficacy from mGluR1 to the intracellular signaling cascades 67 ( Figure 2 ). Otsu et al. showed that mGluR1 activity and Purkinje cell depolarization control climbing fiber-induced Ca 2+ influx 68 . Under basal conditions, climbing fiber stimulation evoked Ca 2+ transients mainly in the proximal dendrites through T-type Ca 2+ channels. Combined mGluR1 activation and depolarization unlocked dendritic Ca 2+ spikes mediated by P/Q-type Ca 2+ channels through inactivation of the A-type K + channels in the distal dendrites of Purkinje cells 68 ( Figure 4 ). These results suggest that climbing fiber-induced Ca 2+ transients can be graded at parallel fiber synapses depending on their activity (i.e. the extent of mGluR1 activation) and therefore give new insight into the mechanisms of LTD induction at parallel fiber synapses. Hartmann et al. demonstrated that both TRPC3-mediated slow EPSC and IP 3 -mediated Ca 2+ release following mGluR1 activation by repetitive parallel fiber stimulation were strongly attenuated in Purkinje cells lacking stromal interaction molecule 1 (STIM1) 69 ( Figure 4 ). In Purkinje cell-specific STIM1-knockout mice, both of the mGluR1-mediated responses were deficient and intracellular Ca 2+ stores were empty 69 . Depolarization of STIM1-deficient Purkinje cells induced normal Ca 2+ entry through voltage-gated Ca 2+ channels, which restored TRPC3-mediated slow EPSC and IP 3 -mediated Ca 2+ release only transiently 69 . Their results indicate that STIM1 is essential for the maintenance of normal Ca 2+ levels in the endoplasmic reticulum at rest and that TRPC3 activation is dependent on intracellular Ca 2+ level and requires interaction with STIM1 ( Figure 4 ). Kato et al. reported that glutamate receptor δ2 (GluRδ2 or GluD2), PKCγ, and TRPC3 are major interactors of mGluR1 by an unbiased proteomic approach 70 . They found that mGluR1-evoked inward currents were increased in a spontaneous mutant mouse line lacking GluD2, which disrupted the time course of mGluR1-dependent synaptic transmission at parallel fiber–Purkinje cell synapses. These results suggest that GluD2 is part of the mGluR1 signaling complex in Purkinje cells. In marked contrast, Ady et al. reported that mGluR1-mediated inward currents induced by repetitive parallel fiber stimulation were markedly reduced in Purkinje cells of another strain of spontaneous GluD2-deficient mice 71 . They also showed that pharmacological blockade and genetic mutation of GluD2 channel pore reduced mGluR1-mediated slow EPSCs and claimed that inward currents through GluD2 channel constituted a significant portion of mGluR1-mediated slow EPSCs 71 . Further studies are necessary to clarify whether and how mGluR1 and GluD2 interact to evoke physiologically relevant responses in Purkinje cells. Dysregulation of mGluR1 signaling in Purkinje cells in cerebellar diseases mGluR1 loss of function in Purkinje cells and cerebellar ataxia Given that genetic deletion of mGluR1 signaling molecules in Purkinje cells causes clear ataxia in mice, many studies have been performed regarding dysregulation of mGluR1 signaling in mouse models of human cerebellar diseases, especially spinocerebellar ataxias (SCAs). In several mouse models of autosomal-dominant SCAs, the expansion of the CAG (Q) trinucleotide repeat disturbs transcription programs in the nucleus. Two types of SCA1 mouse models, SCA1 82Q and SCA1 154Q that express 82 and 154 Q repeats in the human ataxin-1 gene, respectively, have been generated 72 , 73 . In these SCA1 mouse models, loss of retinoid-related orphan receptor alpha (RORα)-mediated signaling leads to the reduced expression of mGluR1, TRPC3, and EAAT4, an excitatory amino acid transporter subtype specific to Purkinje cells 74 – 77 ( Table 1 ). Furthermore, in the spontaneous ataxic mutant mouse staggerer , which exhibits mutation of the RORα gene and therefore is similar to SCA1 mouse models, mGluR1 expression is reduced and mGluR1-mediated slow EPSCs at parallel fiber synapses are deficient 78 ( Table 1 ). In the conditional SCA1 82Q transgenic mouse line (SCA1 82Q Tre/Tre; tTA/tTA) generated by Zu et al. 79 , stopping the expression of mutant ataxin-1 in Purkinje cells restores mGluR1 expression and pathological phenotypes of Purkinje cells as well as motor dysfunction ( Table 1 ). In the SCA1 154Q mouse, decreased mGluR1 expression is accompanied by increased expression of mGluR5, which is normally undetectable in adult wild-type mice 80 ( Table 1 ). This is presumably a compensatory effect that rescues Ca 2+ signaling to prevent Purkinje cell death. Importantly, enhancement of mGluR1 by a positive allosteric modulator (PAM) improves motor coordination in severely ataxic SCA1 154Q mice 80 . This result raises the possibility that mGluR1 PAM could be used to ameliorate ataxia in severe SCA1 patients. Table 1. Mouse models of human cerebellar diseases with type-1 metabotropic glutamate receptor (mGluR1) loss of function. Disease model in mouse Gene mutation Changes in expression/function/ localization Reference SCA1 82Q Ataxin-1 mGluR1 Decreased expression Loss of function Burright et al. 72 Zu et al. 79 Shuvaev et al. 81 SCA1 154Q Ataxin-1 mGluR1 TRPC3 EAAT4 RORα Decreased expression Lin et al. 74 Skinner et al. 77 Watase et al. 73 Serra et al. 75 Serra et al. 76 mGluR5 Increased expression Notartomaso et al. 80 staggerer mutant RORα RORα Decreased expression Mitsumura et al. 78 SCA3 Ataxin-3 mGluR1 RORα Decreased expression Konno et al. 82 SCA5 β-III spectrin mGluR1 Mislocalization Armbrust et al. 83 EAAT4, excitatory amino acid transporter 4; RORα, retinoid-related orphan receptor alpha; TRPC3, short transient receptor potential channel 3. Very recently, Shuvaev et al. 81 reported that the SCA1 82Q mouse line (SCA1-Tg; heterozygous B05 line carrying the human Ataxin-1 gene with 82 Q repeats under the control of the Purkinje cell-specific L7 promoter) generated by Burright et al. 72 exhibited progressive ataxia and impairment in multiple mGluR1 signaling at parallel fiber–Purkinje cell synapses from postnatal week 5 to 12, including TRPC3-mediated slow EPSCs, IP 3 -mediated local Ca 2+ signaling in Purkinje cell dendrites, endocannabinoid-mediated short-term synaptic depression, and LTD 81 ( Table 1 ). Importantly, intraperitoneal administration of a GABA B R agonist, baclofen, restored mGluR1 signaling at parallel fiber–Purkinje cell synapses and ameliorated ataxia of the SCA1 82Q mouse 81 . These results are relevant to the in vitro studies by Kamikubo et al. 57 and raise the possibility of a new therapy for SCA1, since baclofen is a clinically available drug 81 . Expression of mGluR1 is also reduced in SCA3 and SCA5 mouse models. Konno et al. reported that a SCA3 mouse model with disrupted ataxin-3 gene and RORα signaling exhibited impairment of dendritic development and complete loss of mGluR1-dependent endocannabinoid-mediated retrograde suppression of parallel fiber synaptic transmission 82 ( Table 1 ). In a mouse model of SCA5, a mutant form of human β-III spectrin is reported to cause mislocalization of mGluR1 in Purkinje cell dendrites, leading to a functional loss of mGluR1-mediated responses and altered parallel fiber function 83 ( Table 1 ). Taken together, these results suggest that disrupted mGluR1 signaling in Purkinje cells may underlie certain forms of human SCAs. mGluR1 gain of function in Purkinje cells and cerebellar ataxia Recent studies indicate that increased mGluR1 signaling in Purkinje cells could lead to ataxia in several mouse models of human cerebellar dysfunction. Power et al. recently reported that the SCA1 82Q mouse line generated by Zu et al. 79 , which is different from the SCA1 Tg-B05 line originally generated by Burright et al. 72 and used in the recent study by Shuvaev et al. 81 , exhibits reduced motor performance in the rotating rod, reduced complexity of Purkinje cell outer dendrites, decreased height of climbing fiber innervation, and lower frequency of Purkinje cell simple spike firing at 12 weeks of age 84 ( Table 2 ). In contrast to the report by Shuvaev et al. 81 , mGluR1-mediated slow EPSCs and local Ca 2+ transients in dendrites induced by repetitive parallel fiber stimulation were both prolonged in SCA1 82Q Purkinje cells without significant changes in their amplitudes 84 . Remarkably, administration of a negative allosteric modulator (NAM) of mGluR1 shortened the two forms of mGluR1-mediated synaptic responses and ameliorated the ataxia 84 . These data suggest that mGluR1 gain of function may underlie the pathophysiology of early stage SCA1. However, the data should be interpreted with caution. Power et al. reported that blockade of astroglial glutamate transporters, which markedly enhances the amplitude and the duration of mGluR1-mediated slow EPSPs in control mice, had no effect in the SCA1 82Q mouse line 84 . This result suggests that glutamate uptake by Bergmann glia may be severely impaired in the SCA1 82Q mouse line used by Power et al. and, therefore, mGluR1-mediated slow EPSPs may be prolonged, even though mGluR1 signaling itself might be impaired in Purkinje cells similarly to those of the SCA1 Tg-B05 line used by Shuvaev et al. 81 Table 2. Mouse models of human cerebellar diseases with type-1 metabotropic glutamate receptor (mGluR1) gain of function. Disease model in mouse Gene mutation Changes in expression/function Reference SCA1 82Q (early stage) Ataxin-1 mGluR1 Gain of function Power et al. 84 SCA2 58Q Ataxin-2 IP3R Increased sensitivity Liu et al. 85 moonwalker mutant TRPC3 TRPC3 Hyperactive Becker et al. 87 SCA14 PKCγ TRPC3 Hyperactive Shuvaev et al. 88 IP 3 R, inositol trisphosphate receptor; PKCγ, protein kinase C gamma; TRPC3, short transient receptor potential channel 3. In the SCA2 58Q mouse model, mGluR1-induced Ca 2+ mobilization through IP 3 R is enhanced in Purkinje cells because of specific binding of mutant ataxin-2 to IP 3 R and elevation of its sensitivity to IP 3 85 ( Table 2 ). Viral delivery of the IP 3 degradation enzyme IP 3 phosphatase rescued age-dependent motor incoordination and Purkinje cell loss in the SCA2 58Q mouse model 86 . The spontaneous ataxic mutant mouse moonwalker exhibits hyperactive mGluR1-mediated TRPC3 currents in Purkinje cells 87 ( Table 2 ). This mouse line has a threonine to alanine switch in TRPC3 that allows the cation channel to open under conditions of weaker mGluR1 activation 87 . On the other hand, a mouse model of SCA14 has larger mGluR1-mediated inward currents in Purkinje cells than do normal mice because of the failure to inactivate TRPC3 by mutant PKCγ 88 ( Table 2 ). These results suggest that increased Na + and Ca 2+ influx through TRPC3 channels disrupts normal functions of Purkinje cells and other cerebellar neurons, which causes ataxia. Dysregulation of mGluR1 signaling in human ataxias There are several reports supporting the notion that altered mGluR1 signaling in Purkinje cells is related to human cerebellar diseases. Patients who express autoantibodies against mGluR1 89 or Homer-3, a scaffolding protein for mGluRs 90 , exhibit ataxia. Mutations in mGluR1 91 and TRPC3 have been reported to occur in patients with rare, early onset autosomal-recessive ataxias 92 . It has been reported that SCA15 is caused by a mutation in the gene encoding the IP 3 R 93 , whereas SCA14 results from mutations in PKCγ that render this enzyme constitutively active 94 . These studies suggest that dysregulation of mGluR1 signaling in Purkinje cells may lead to human ataxias. Closing remarks In recent years, several molecules that interact directly with mGluR1 or function downstream of mGluR1 have been identified, and their modes of action have been investigated. These include GluD2 70 , 71 , TRPC3 44 , 70 , STIM1 69 , GABA B R 56 , 57 , 95 , A1R 60 , 67 , Ca V 3.1 T-type Ca 2+ channel 63 , and A-type K + channel 68 . It has also become clear that the activation of mGluR1 at parallel fiber–Purkinje cell synapses exerts multiple effects that can induce both elevation and suppression of Purkinje cell activity. These results derive from well-controlled experiments in reduced preparations in which individual phenomena can be isolated either genetically or pharmacologically. It is important to investigate how these multiple effects induced by mGluR1 activation contribute to the net activity of Purkinje cells, development of synaptic wiring onto Purkinje cells, and overall cerebellar function. For this purpose, it would be necessary to examine Purkinje cell responses in intact cerebellum in vivo from mice in which a specific mGluR1 signaling molecule has been genetically modified or deleted. In vivo whole-cell recording combined with single-cell Ca 2+ imaging has been used to record Purkinje cell activity and climbing fiber-mediated responses from intact cerebellum 96 . It would also be important to record activities from populations of Purkinje cells in vivo and analyze their spatiotemporal correlations to investigate the network function of the cerebellum. Genetically encoded calcium indicators and Ca 2+ imaging with a two-photon microscope have been used to monitor climbing fiber-mediated responses from populations of Purkinje cells 97 . On the other hand, since it is not possible to register simple spike activities of Purkinje cells by Ca 2+ imaging, conventional extracellular recording is still important. Another important issue would be the possible diversity of Purkinje cells, other cell types, and neural circuits in different regions of the cerebellum. It has been widely assumed that properties of synaptic transmission, synaptic plasticity, and developmental synaptic refinement, which are mostly based on studies in slice preparations from the cerebellar vermis, apply throughout the cerebellum. However, clear differences exist in gene expression, Purkinje cell firing rates, and behavioral functions of different cerebellar regions 98 . In this context, Surrathan et al. 99 recently reported that proper timing between parallel fiber and climbing fiber inputs for LTD induction is different in different regions of the cerebellum such that synaptic plasticity can precisely compensate for behaviorally relevant circuit delays 99 . Thus, it would be important to investigate whether the same signaling pathways including mGluR1 and its related molecules contribute to LTD in different regions of the cerebellum and how the diversity of synaptic plasticity is produced. Alteration of mGluR1 signaling has been reported in various clinically relevant mouse models of human cerebellar diseases 24 , 30 . Judging from the severe cerebellar dysfunctions of mGluR1-knockout mice, it is conceivable that mGluR1 loss-of-function underlies human ataxias 74 – 78 , 80 , 82 , 83 . However, it is important to note that mGluR1 gain-of-function has been reported in certain mouse models of human ataxias 84 – 88 . Calcium overload to Purkinje cells due to excess mGluR1-mediated Ca 2+ release and/or TRPC3 channel activation is likely to cause cerebellar dysfunction. In such mouse models, down-regulation of mGluR1 signaling molecules may occur to compensate for its hyperactivity with the progress of disease. Thus, it is important to determine whether the mGluR1 loss-of function is the cause or the result of such cerebellar diseases. Given that the recent development of mGluR1 PAM and NAM have raised the possibility of treating cerebellar ataxias, it is important to determine whether mGluR1 signaling is up- or down-regulated at a particular stage of cerebellar ataxia. In addition, a very recent report suggests that baclofen, a clinically available GABA B R agonist, can ameliorate cerebellar dysfunction by enhancing mGluR1 signaling in a SCA1 model mouse line 81 . Careful examination of the mouse models with the progress of cerebellar symptoms would be necessary. Competing interests The authors declare that they have no competing interests. Grant information This work was supported by the Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (grant 25000015), and the Brain/MINDS grant from the Japan Agency for Medical Research and Development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgements We thank Naofumi Uesaka for helpful discussion on this manuscript. Faculty Opinions recommended References 1. Ito M: The CEREBELLUM and NEURAL CONTROL. (Raven Press, New York) 1984. Reference Source 2. Ito M: Control of mental activities by internal models in the cerebellum. Nat Rev Neurosci. 2008; 9 (4): 304–13. PubMed Abstract | Publisher Full Text 3. Eccles JC, Ito M, Szentagothai J: The Cerebellum as a Neuronal Machine. (Springer-Verlag, Berlin / Heidelberg / New York) 1967. Publisher Full Text 4. Palay SL, Chan-Palay V: Cerebellar Cortex. (Springer-Verlag, New York) 1974. Publisher Full Text 5. Ito M: Cerebellar long-term depression: characterization, signal transduction, and functional roles. Physiol Rev. 2001; 81 (3): 1143–95. PubMed Abstract 6. Ito M, Sakurai M, Tongroach P: Climbing fibre induced depression of both mossy fibre responsiveness and glutamate sensitivity of cerebellar Purkinje cells. J Physiol. 1982; 324 : 113–34. PubMed Abstract | Publisher Full Text | Free Full Text 7. Hashimoto K, Kano M: Postnatal development and synapse elimination of climbing fiber to Purkinje cell projection in the cerebellum. Neurosci Res. 2005; 53 (3): 221–8. PubMed Abstract | Publisher Full Text 8. Hashimoto K, Kano M: Synapse elimination in the developing cerebellum. Cell Mol Life Sci. 2013; 70 (24): 4667–80. PubMed Abstract | Publisher Full Text | Free Full Text 9. Huang ZJ: Activity-dependent development of inhibitory synapses and innervation pattern: role of GABA signalling and beyond. J Physiol. 2009; 587 (Pt 9): 1881–8. PubMed Abstract | Publisher Full Text | Free Full Text 10. Huang ZJ, Di Cristo G, Ango F: Development of GABA innervation in the cerebral and cerebellar cortices. Nat Rev Neurosci. 2007; 8 (9): 673–86. PubMed Abstract | Publisher Full Text 11. Kano M, Nakayama H, Hashimoto K, et al. : Calcium-dependent regulation of climbing fibre synapse elimination during postnatal cerebellar development. J Physiol. 2013; 591 (13): 3151–8. PubMed Abstract | Publisher Full Text | Free Full Text 12. Kano M, Watanabe M: Synaptogenesis and Synapse Elimination. In Handbook of Cerebellum and Cerebellar Disorders (eds. Manto, M., Gruol, D., Schmahmann, J., Koibuchi, N. & Rossi, F.) (Springer, New York, Heidelberg, Dordrecht, London) 2013; 281–299. Publisher Full Text 13. Williams ME, de Wit J, Ghosh A: Molecular mechanisms of synaptic specificity in developing neural circuits. Neuron. 2010; 68 (1): 9–18. PubMed Abstract | Publisher Full Text | Free Full Text 14. Yuzaki M: Cbln1 and its family proteins in synapse formation and maintenance. Curr Opin Neurobiol. 2011; 21 (2): 215–20. PubMed Abstract | Publisher Full Text 15. Conn PJ, Pin JP: Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol. 1997; 37 : 205–37. PubMed Abstract | Publisher Full Text 16. Nakanishi S: Metabotropic glutamate receptors: synaptic transmission, modulation, and plasticity. Neuron. 1994; 13 (5): 1031–7. PubMed Abstract | Publisher Full Text 17. Baude A, Nusser Z, Roberts JD, et al. : The metabotropic glutamate receptor (mGluR1 α) is concentrated at perisynaptic membrane of neuronal subpopulations as detected by immunogold reaction. Neuron. 1993; 11 (4): 771–87. PubMed Abstract | Publisher Full Text 18. Fotuhi M, Sharp AH, Glatt CE, et al. : Differential localization of phosphoinositide-linked metabotropic glutamate receptor (mGluR1) and the inositol 1,4,5-trisphosphate receptor in rat brain. J Neurosci. 1993; 13 (5): 2001–12. PubMed Abstract 19. Masu M, Tanabe Y, Tsuchida K, et al. : Sequence and expression of a metabotropic glutamate receptor. Nature. 1991; 349 (6312): 760–5. PubMed Abstract | Publisher Full Text 20. Shigemoto R, Nakanishi S, Mizuno N: Distribution of the mRNA for a metabotropic glutamate receptor (mGluR1) in the central nervous system: an in situ hybridization study in adult and developing rat. J Comp Neurol. 1992; 322 (1): 121–35. PubMed Abstract | Publisher Full Text 21. Gao Z, van Beugen BJ, De Zeeuw CI: Distributed synergistic plasticity and cerebellar learning. Nat Rev Neurosci. 2012; 13 (9): 619–35. PubMed Abstract | Publisher Full Text 22. Ito M: The molecular organization of cerebellar long-term depression. Nat Rev Neurosci. 2002; 3 (11): 896–902. PubMed Abstract | Publisher Full Text 23. Kano M, Hashimoto K, Tabata T: Type-1 metabotropic glutamate receptor in cerebellar Purkinje cells: a key molecule responsible for long-term depression, endocannabinoid signalling and synapse elimination. Philos Trans R Soc Lond B Biol Sci. 2008; 363 (1500): 2173–86. PubMed Abstract | Publisher Full Text | Free Full Text 24. Power EM, English NA, Empson RM: Are Type 1 metabotropic glutamate receptors a viable therapeutic target for the treatment of cerebellar ataxia? J Physiol. 2016; 594 (16): 4643–52. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 25. Aiba A, Kano M, Chen C, et al. : Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice. Cell. 1994; 79 (2): 377–88. PubMed Abstract | Publisher Full Text 26. Conquet F, Bashir ZI, Davies CH, et al. : Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1. Nature. 1994; 372 (6503): 237–43. PubMed Abstract | Publisher Full Text 27. Kano M, Hashimoto K, Kurihara H, et al. : Persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking mGluR1. Neuron. 1997; 18 (1): 71–9. PubMed Abstract | Publisher Full Text 28. Ichise T, Kano M, Hashimoto K, et al. : mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination. Science. 2000; 288 (5472): 1832–5. PubMed Abstract | Publisher Full Text 29. Ohtani Y, Miyata M, Hashimoto K, et al. : The synaptic targeting of mGluR1 by its carboxyl-terminal domain is crucial for cerebellar function. J Neurosci. 2014; 34 (7): 2702–12. PubMed Abstract | Publisher Full Text 30. Meera P, Pulst SM, Otis TS: Cellular and circuit mechanisms underlying spinocerebellar ataxias. J Physiol. 2016; 594 (16): 4653–60. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 31. Ito M: Cerebellar control of the vestibulo-ocular reflex--around the flocculus hypothesis. Annu Rev Neurosci. 1982; 5 : 275–96. PubMed Abstract | Publisher Full Text 32. Levenes C, Daniel H, Jaillard D, et al. : Incomplete regression of multiple climbing fibre innervation of cerebellar Purkinje cells in mGLuR1 mutant mice. Neuroreport. 1997; 8 (2): 571–4. PubMed Abstract | Publisher Full Text 33. Crepel F: Regression of functional synapses in the immature mammalian cerebellum. Trends Neurosci. 1982; 5 : 266–9. Publisher Full Text 34. Kano M, Hashimoto K: Synapse elimination in the central nervous system. Curr Opin Neurobiol. 2009; 19 (2): 154–61. PubMed Abstract | Publisher Full Text 35. Lohof AM, Delhaye-Bouchaud N, Mariani J: Synapse elimination in the central nervous system: functional significance and cellular mechanisms. Rev Neurosci. 1996; 7 (2): 85–101. PubMed Abstract | Publisher Full Text 36. Watanabe M, Kano M: Climbing fiber synapse elimination in cerebellar Purkinje cells. Eur J Neurosci. 2011; 34 (10): 1697–710. PubMed Abstract | Publisher Full Text 37. Kano M, Hashimoto K, Chen C, et al. : Impaired synapse elimination during cerebellar development in PKC γ mutant mice. Cell. 1995; 83 (7): 1223–31. PubMed Abstract | Publisher Full Text 38. Kano M, Hashimoto K, Watanabe M, et al. : Phospholipase Cβ4 is specifically involved in climbing fiber synapse elimination in the developing cerebellum. Proc Natl Acad Sci U S A. 1998; 95 (26): 15724–9. PubMed Abstract | Publisher Full Text | Free Full Text 39. Offermanns S, Hashimoto K, Watanabe M, et al. : Impaired motor coordination and persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking Gαq. Proc Natl Acad Sci U S A. 1997; 94 (25): 14089–94. PubMed Abstract | Publisher Full Text | Free Full Text 40. Piochon C, Kano M, Hansel C: LTD-like molecular pathways in developmental synaptic pruning. Nat Neurosci. 2016; 19 (10): 1299–310. PubMed Abstract | Publisher Full Text | Free Full Text 41. Batchelor AM, Garthwaite J: Frequency detection and temporally dispersed synaptic signal association through a metabotropic glutamate receptor pathway. Nature. 1997; 385 (6611): 74–7. PubMed Abstract | Publisher Full Text 42. Batchelor AM, Madge DJ, Garthwaite J: Synaptic activation of metabotropic glutamate receptors in the parallel Fibre-Purkinje cell pathway in rat cerebellar slices. Neuroscience. 1994; 63 (4): 911–5. PubMed Abstract | Publisher Full Text 43. Tempia F, Alojado ME, Strata P, et al. : Characterization of the mGluR1-mediated electrical and calcium signaling in Purkinje cells of mouse cerebellar slices. J Neurophysiol. 2001; 86 (3): 1389–97. PubMed Abstract 44. Hartmann J, Dragicevic E, Adelsberger H, et al. : TRPC3 channels are required for synaptic transmission and motor coordination. Neuron. 2008; 59 (3): 392–8. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 45. Finch EA, Augustine GJ: Local calcium signalling by inositol-1,4,5-trisphosphate in Purkinje cell dendrites. Nature. 1998; 396 (6713): 753–6. PubMed Abstract | Publisher Full Text 46. Takechi H, Eilers J, Konnerth A: A new class of synaptic response involving calcium release in dendritic spines. Nature. 1998; 396 (6713): 757–60. PubMed Abstract | Publisher Full Text 47. Brenowitz SD, Regehr WG: Associative short-term synaptic plasticity mediated by endocannabinoids. Neuron. 2005; 45 (3): 419–31. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 48. Brown SP, Brenowitz SD, Regehr WG: Brief presynaptic bursts evoke synapse-specific retrograde inhibition mediated by endogenous cannabinoids. Nat Neurosci. 2003; 6 (10): 1048–57. PubMed Abstract | Publisher Full Text 49. Maejima T, Hashimoto K, Yoshida T, et al. : Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron. 2001; 31 (3): 463–75. PubMed Abstract | Publisher Full Text 50. Maejima T, Oka S, Hashimotodani Y, et al. : Synaptically driven endocannabinoid release requires Ca 2+ -assisted metabotropic glutamate receptor subtype 1 to phospholipase Cβ4 signaling cascade in the cerebellum. J Neurosci. 2005; 25 (29): 6826–35. PubMed Abstract | Publisher Full Text 51. Gao Y, Vasilyev DV, Goncalves MB, et al. : Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. J Neurosci. 2010; 30 (6): 2017–24. PubMed Abstract | Publisher Full Text 52. Tanimura A, Yamazaki M, Hashimotodani Y, et al. : The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase α mediates retrograde suppression of synaptic transmission. Neuron. 2010; 65 (3): 320–7. PubMed Abstract | Publisher Full Text 53. Carey MR, Myoga MH, McDaniels KR, et al. : Presynaptic CB 1 receptors regulate synaptic plasticity at cerebellar parallel fiber synapses. J Neurophysiol. 2011; 105 (2): 958–63. PubMed Abstract | Publisher Full Text | Free Full Text 54. Safo PK, Regehr WG: Endocannabinoids control the induction of cerebellar LTD. Neuron. 2005; 48 (4): 647–59. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 55. Kishimoto Y, Kano M: Endogenous cannabinoid signaling through the CB 1 receptor is essential for cerebellum-dependent discrete motor learning. J Neurosci. 2006; 26 (34): 8829–37. PubMed Abstract | Publisher Full Text 56. Hirono M, Yoshioka T, Konishi S: GABA B receptor activation enhances mGluR-mediated responses at cerebellar excitatory synapses. Nat Neurosci. 2001; 4 (12): 1207–16. PubMed Abstract | Publisher Full Text 57. Kamikubo Y, Tabata T, Kakizawa S, et al. : Postsynaptic GABA B receptor signalling enhances LTD in mouse cerebellar Purkinje cells. J Physiol. 2007; 585 (Pt 2): 549–63. PubMed Abstract | Publisher Full Text | Free Full Text 58. Tabata T, Araishi K, Hashimoto K, et al. : Ca 2+ activity at GABA B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA. Proc Natl Acad Sci U S A. 2004; 101 (48): 16952–7. PubMed Abstract | Publisher Full Text | Free Full Text 59. Tabata T, Aiba A, Kano M: Extracellular calcium controls the dynamic range of neuronal metabotropic glutamate receptor responses. Mol Cell Neurosci. 2002; 20 (1): 56–68. PubMed Abstract | Publisher Full Text 60. Tabata T, Kawakami D, Hashimoto K, et al. : G protein-independent neuromodulatory action of adenosine on metabotropic glutamate signalling in mouse cerebellar Purkinje cells. J Physiol. 2007; 581 (Pt 2): 693–708. PubMed Abstract | Publisher Full Text | Free Full Text 61. Canepari M, Ogden D: Kinetic, pharmacological and activity-dependent separation of two Ca 2+ signalling pathways mediated by type 1 metabotropic glutamate receptors in rat Purkinje neurones. J Physiol. 2006; 573 (Pt 1): 65–82. PubMed Abstract | Publisher Full Text | Free Full Text 62. Khodakhah K, Ogden D: Functional heterogeneity of calcium release by inositol trisphosphate in single Purkinje neurones, cultured cerebellar astrocytes, and peripheral tissues. Proc Natl Acad Sci U S A. 1993; 90 (11): 4976–80. PubMed Abstract | Publisher Full Text | Free Full Text 63. Hildebrand ME, Isope P, Miyazaki T, et al. : Functional coupling between mGluR1 and Ca v 3.1 T-type calcium channels contributes to parallel fiber-induced fast calcium signaling within Purkinje cell dendritic spines. J Neurosci. 2009; 29 (31): 9668–82. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 64. Chae HG, Ahn SJ, Hong YH, et al. : Transient receptor potential canonical channels regulate the induction of cerebellar long-term depression. J Neurosci. 2012; 32 (37): 12909–14. PubMed Abstract | Publisher Full Text 65. Uesaka N, Uchigashima M, Mikuni T, et al. : Retrograde semaphorin signaling regulates synapse elimination in the developing mouse brain. Science. 2014; 344 (6187): 1020–3. PubMed Abstract | Publisher Full Text 66. Ichikawa R, Hashimoto K, Miyazaki T, et al. : Territories of heterologous inputs onto Purkinje cell dendrites are segregated by mGluR1-dependent parallel fiber synapse elimination. Proc Natl Acad Sci U S A. 2016; 113 (8): 2282–7. PubMed Abstract | Publisher Full Text | Free Full Text 67. Kamikubo Y, Shimomura T, Fujita Y, et al. : Functional cooperation of metabotropic adenosine and glutamate receptors regulates postsynaptic plasticity in the cerebellum. J Neurosci. 2013; 33 (47): 18661–71. PubMed Abstract | Publisher Full Text 68. Otsu Y, Marcaggi P, Feltz A, et al. : Activity-dependent gating of calcium spikes by A-type K+ channels controls climbing fiber signaling in Purkinje cell dendrites. Neuron. 2014; 84 (1): 137–51. PubMed Abstract | Publisher Full Text | Free Full Text 69. Hartmann J, Karl RM, Alexander RP, et al. : STIM1 controls neuronal Ca 2+ signaling, mGluR1-dependent synaptic transmission, and cerebellar motor behavior. Neuron. 2014; 82 (3): 635–44. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 70. Kato AS, Knierman MD, Siuda ER, et al. : Glutamate receptor δ2 associates with metabotropic glutamate receptor 1 (mGluR1), protein kinase Cγ, and canonical transient receptor potential 3 and regulates mGluR1-mediated synaptic transmission in cerebellar Purkinje neurons. J Neurosci. 2012; 32 (44): 15296–308. PubMed Abstract | Publisher Full Text 71. Ady V, Perroy J, Tricoire L, et al. : Type 1 metabotropic glutamate receptors (mGlu1) trigger the gating of GluD2 δ glutamate receptors. EMBO Rep. 2014; 15 (1): 103–9. PubMed Abstract | Publisher Full Text | Free Full Text 72. Burright EN, Clark HB, Servadio A, et al. : SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell. 1995; 82 (6): 937–48. PubMed Abstract | Publisher Full Text 73. Watase K, Weeber EJ, Xu B, et al. : A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron. 2002; 34 (6): 905–19. PubMed Abstract | Publisher Full Text 74. Lin X, Antalffy B, Kang D, et al. : Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat Neurosci. 2000; 3 (2): 157–63. PubMed Abstract | Publisher Full Text 75. Serra HG, Byam CE, Lande JD, et al. : Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum Mol Genet. 2004; 13 (20): 2535–43. PubMed Abstract | Publisher Full Text 76. Serra HG, Duvick L, Zu T, et al. : RORα-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell. 2006; 127 (4): 697–708. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 77. Skinner PJ, Vierra-Green CA, Clark HB, et al. : Altered trafficking of membrane proteins in Purkinje cells of SCA1 transgenic mice. Am J Pathol. 2001; 159 (3): 905–13. PubMed Abstract | Publisher Full Text | Free Full Text 78. Mitsumura K, Hosoi N, Furuya N, et al. : Disruption of metabotropic glutamate receptor signalling is a major defect at cerebellar parallel fibre-Purkinje cell synapses in staggerer mutant mice. J Physiol. 2011; 589 (Pt 13): 3191–209. PubMed Abstract | Publisher Full Text | Free Full Text 79. Zu T, Duvick LA, Kaytor MD, et al. : Recovery from polyglutamine-induced neurodegeneration in conditional SCA1 transgenic mice. J Neurosci. 2004; 24 (40): 8853–61. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 80. Notartomaso S, Zappulla C, Biagioni F, et al. : Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1. Mol Brain. 2013; 6 : 48. PubMed Abstract | Publisher Full Text | Free Full Text 81. Shuvaev AN, Hosoi N, Sato Y, et al. : Progressive impairment of cerebellar mGluR signalling and its therapeutic potential for cerebellar ataxia in spinocerebellar ataxia type 1 model mice. J Physiol. 2017; 595 (1): 141–64. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 82. Konno A, Shuvaev AN, Miyake N, et al. : Mutant ataxin-3 with an abnormally expanded polyglutamine chain disrupts dendritic development and metabotropic glutamate receptor signaling in mouse cerebellar Purkinje cells. Cerebellum. 2014; 13 (1): 29–41. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 83. Armbrust KR, Wang X, Hathorn TJ, et al. : Mutant β-III spectrin causes mGluR1α mislocalization and functional deficits in a mouse model of spinocerebellar ataxia type 5. J Neurosci. 2014; 34 (30): 9891–904. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 84. Power EM, Morales A, Empson RM: Prolonged Type 1 Metabotropic Glutamate Receptor Dependent Synaptic Signaling Contributes to Spino-Cerebellar Ataxia Type 1. J Neurosci. 2016; 36 (18): 4910–6. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 85. Liu J, Tang TS, Tu H, et al. : Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 2. J Neurosci. 2009; 29 (29): 9148–62. PubMed Abstract | Publisher Full Text | Free Full Text 86. Kasumu AW, Liang X, Egorova P, et al. : Chronic suppression of inositol 1,4,5-triphosphate receptor-mediated calcium signaling in cerebellar Purkinje cells alleviates pathological phenotype in spinocerebellar ataxia 2 mice. J Neurosci. 2012; 32 (37): 12786–96. PubMed Abstract | Publisher Full Text | Free Full Text 87. Becker EB, Oliver PL, Glitsch MD, et al. : A point mutation in TRPC3 causes abnormal Purkinje cell development and cerebellar ataxia in moonwalker mice. Proc Natl Acad Sci U S A. 2009; 106 (16): 6706–11. PubMed Abstract | Publisher Full Text | Free Full Text 88. Shuvaev AN, Horiuchi H, Seki T, et al. : Mutant PKCγ in spinocerebellar ataxia type 14 disrupts synapse elimination and long-term depression in Purkinje cells in vivo . J Neurosci. 2011; 31 (40): 14324–34. PubMed Abstract | Publisher Full Text 89. Sillevis Smitt P, Kinoshita A, De Leeuw B, et al. : Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med. 2000; 342 (1): 21–7. PubMed Abstract | Publisher Full Text 90. Höftberger R, Sabater L, Ortega A, et al. : Patient with homer-3 antibodies and cerebellitis. JAMA Neurol. 2013; 70 (4): 506–9. PubMed Abstract | Publisher Full Text | Free Full Text 91. Guergueltcheva V, Azmanov DN, Angelicheva D, et al. : Autosomal-recessive congenital cerebellar ataxia is caused by mutations in metabotropic glutamate receptor 1. Am J Hum Genet. 2012; 91 (3): 553–64. PubMed Abstract | Publisher Full Text | Free Full Text 92. Fogel BL, Hanson SM, Becker EB: Do mutations in the murine ataxia gene TRPC3 cause cerebellar ataxia in humans? Mov Disord. 2015; 30 (2): 284–6. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 93. van de Leemput J, Chandran J, Knight MA, et al. : Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet. 2007; 3 (6): e108. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 94. Yabe I, Sasaki H, Chen DH, et al. : Spinocerebellar ataxia type 14 caused by a mutation in protein kinase C γ. Arch Neurol. 2003; 60 (12): 1749–51. PubMed Abstract | Publisher Full Text 95. Tabata T, Kano M: Calcium dependence of native metabotropic glutamate receptor signaling in central neurons. Mol Neurobiol. 2004; 29 (3): 261–70. PubMed Abstract | Publisher Full Text 96. Kitamura K, Häusser M: Dendritic calcium signaling triggered by spontaneous and sensory-evoked climbing fiber input to cerebellar Purkinje cells in vivo . J Neurosci. 2011; 31 (30): 10847–58. PubMed Abstract | Publisher Full Text | Free Full Text 97. Tsutsumi S, Yamazaki M, Miyazaki T, et al. : Structure-function relationships between aldolase C/zebrin II expression and complex spike synchrony in the cerebellum. J Neurosci. 2015; 35 (2): 843–52. PubMed Abstract | Publisher Full Text 98. Cerminara NL, Lang EJ, Sillitoe RV, et al. : Redefining the cerebellar cortex as an assembly of non-uniform Purkinje cell microcircuits. Nat Rev Neurosci. 2015; 16 (2): 79–93. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 99. Suvrathan A, Payne HL, Raymond JL: Timing Rules for Synaptic Plasticity Matched to Behavioral Function. Neuron. 2016; 92 (5): 959–67. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 04 Apr 2017 ADD YOUR COMMENT Comment Author details Author details 1 Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan Competing interests The authors declare that they have no competing interests. Grant information This work was supported by the Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (grant 25000015), and the Brain/MINDS grant from the Japan Agency for Medical Research and Development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (1) version 1 Published: 04 Apr 2017, 6:416 https://doi.org/10.12688/f1000research.10485.1 Copyright © 2017 Kano M and Watanabe T. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication). Download Export To Sciwheel Bibtex EndNote ProCite Ref. 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Reviewers who approved this article Alanna Watt , Department of Biology, McGill University, Canada Competing interests: No competing interests were declared. (for version 1) Visou Ady , Department of Biology, McGill University, Canada Competing interests: No competing interests were declared. (for version 1) Maria Concetta Miniaci , Department of Pharmacy, University of Naples Federico II, Italy Competing interests: No competing interests were declared. (for version 1) Ferdinando Nicoletti , Department of Physiology and Pharmacology, Sapienza University of Rome, Italy; I.R.C.C.S. Neuromed, Italy Competing interests: No competing interests were declared. (for version 1) Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 04 Apr 2017 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 1 04 Apr 17 Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Alanna Watt , Department of Biology, McGill University, Canada Competing interests: No competing interests were declared. View more View less Visou Ady , Department of Biology, McGill University, Canada Competing interests: No competing interests were declared. View more View less Maria Concetta Miniaci , Department of Pharmacy, University of Naples Federico II, Italy Competing interests: No competing interests were declared. View more View less Ferdinando Nicoletti , Department of Physiology and Pharmacology, Sapienza University of Rome, Italy; I.R.C.C.S. Neuromed, Italy Competing interests: No competing interests were declared. 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