Impaired metabotropic glutamate type 5 receptor signaling in the dorsal striatum of the R451C-neuroligin 3 mouse model of Autism Spectrum Disorder

Impaired metabotropic glutamate type 5 receptor signaling in the dorsal striatum of the R451C-neuroligin 3 mouse model of Autism Spectrum Disorder | 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 Research Article Impaired metabotropic glutamate type 5 receptor signaling in the dorsal striatum of the R451C-neuroligin 3 mouse model of Autism Spectrum Disorder Maria Meringolo, Martina Montanari, Simona D'Antoni, Giuseppina Martella, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4893764/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Human genetics indicates enrichment of synaptic pathway-related mutations in Autism Spectrum Disorder (ASD). Accordingly, several preclinical studies have reported synaptic alterations in different brain areas of relevant ASD mouse models. In particular, we previously showed that corticostriatal long-term synaptic depression is impaired in the dorsal striatum of mice carrying the ASD-associated R451C mutation in the NL3 gene, coding for the postsynaptic protein neuroligin 3. Here, we used behavioral, proteomic, biochemical, and electrophysiological approaches to explore the dorsal striatum-dependent functions in the R451C-NL3 knock-in mouse model of ASD. A detailed behavioral analysis confirmed striatum-dependent alterations in these mice. We further explored the synaptic function in the dorsal striatum, disclosing modifications of the glutamatergic postsynaptic density protein composition and the impairment of different forms of corticostriatal long-term synaptic plasticity involving the activation of group I metabotropic glutamate receptors, namely activity-dependent depression and potentiation, and pharmacological 3,5-DHPG-induced synaptic depression. Notably, activation of group I metabotropic glutamate receptors was not able to potentiate NMDA receptor-mediated currents. Protein expression levels of type 5 metabotropic glutamate receptor were reduced at striatal synapses, whereas the protein level and function of glutamate ionotropic receptors were unaltered. Overall, our findings point to a significant impairment of metabotropic glutamate receptor type 5 signaling in neuroligin 3 knock-in mice, affecting the dorsal striatum circuitry, that has been implicated in several autism-related behaviors. Behavior proteomics electrophysiology glutamate metabotropic receptors corticostriatal synapses Full Text Additional Declarations The authors declare no competing interests. Supplementary Files suppl.figure1.tif Supplementary Figure 1. Social behaviors: (Top) Cartoon of the 3-chamber apparatus in the two phases of the test. A1) Amount of time spent interacting with the social stimulus (SOC) or non-social stimulus (OBJ) in WT versus R451C-NL3 mice (Interaction time: WT object = 60.08 ± 6.811s, WT social = 104.8 ± 10.81s, N= 10, Sidak’s multiple comparisons test *p = 0.018; R451C-NL3 object = 75.20 ± 10.16s; R451C-NL3 social = 80.11 ± 12.42s, N= 9, Sidak’s multiple comparisons test p = 0.9997; two-way ANOVA, F(1,34) interaction = 5.978, P = 0.448). A2) Bar graph of the social preference index of control and R451C-NL3 mice (WT social preference index = 0.633 ± 0.028, R451C-NL3 social preference index = 0.509 ± 0.038; unpaired t-test *p = 0.018). A3) Amount of time spent interacting with the novel stimulus (NOV) or the familiar stimulus (FAM) in the novelty phase of the test (Interaction time: WT familiar = 60.79 ± 7.317s, WT novel = 104.5 ± 15.46s, N= 10, Sidak’s multiple comparisons test, *p = 0.037; R451C-NL3 familiar = 76.54 ± 8.005s; R451C-NL3 novel = 52.41 ± 10.12s, N= 9, Sidak’s multiple comparisons test, p = 0.586; two-way ANOVA, F(1,34) interaction = 9.670, **p = 0.0038). A4) Bar graph of the novel preference index of WT and R451C-NL3 mice (WT novel preference index = 0.615 ± 0.049, R451C-NL3 novel preference index = 0.400 ± 0.056; Mann-Whitney test *p = 0.017). Anhedonia: (Top) Cartoon of the sucrose splash test. B1) Number of dorsal self-grooming (WT= 10.42 ± 0.857, N= 12; R451C-NL3= 7.8 ± 0.841, N= 10; unpaired t-test *p = 0.043) and (B2) latency to the first grooming of R451C-NL3 mice and their WT littermates (WT= 38.75 ± 7.072 s, N= 12; R451C-NL3= 41.70 ± 6.414 s, N= 10; unpaired t-test p = 0.765). Cognitive function: C) Novel object recognition test (NORT). (C1) Summary plots depicting the amount of time spent interacting with the familiar (FAM) or the novel (NOV) object during the test session (WT familiar = 13.78 ± 1.286 s, WT novel = 24.56 ± 2.235 s, N= 12; Sidak’s multiple comparisons test, **p = 0.003; R451C-NL3 familiar = 16.54 ± 2.124 s; R451C-NL3 novel = 29.91 ± 2.660 s, N= 10; Sidak’s multiple comparisons test, ***p = 0.0006; one-way ANOVA, F= 12.29, ****p < 0.0001). (C2) Bar chart reporting the discrimination index for the novel object (WT= 0.265 ± 0.048, N= 12; R451C-NL3= 0.298 ± 0.056, N= 10; unpaired t-test p = 0.655). D) Y maze test. The summary plots report (D1) the percentage of spontaneous alternations (WT= 59.32 ± 2.666 %, N= 12; R451C-NL3= 53.80 ± 2.613 %, N= 10; unpaired t-test p = 0.159), and (D2) the total number of entries in the three arms of the Y maze apparatus (WT= 49.83 ± 2.719, N= 12; R451C-NL3= 63.00 ± 3.836, N= 10; unpaired t-test **p = 0.009). Anxiety behaviors: E) Open field test. (E1) Bar charts reporting the time spent in the center of the arena (WT= 222.7 ± 22.92 s, N= 12; R451C-NL3= 260.8 ± 25.21 s, N= 10; unpaired t-test p = 0.276), (E2) number of entries in the center zone (WT= 46.25 ± 4.799, N= 12; R451C-NL3= 59.20 ± 5.974, N= 10; unpaired t-test p = 0.103) and (E3) number of defecations during the session (WT= 6.0 ± 0.835, N= 12; R451C-NL3= 7.7 ± 0.731, N= 10; unpaired t-test p = 0.149). F) Elevated plus maze (EPM). (F1) Summary plots comparing the number of entries of mice in the open (OA) vs. the closed arms (CA) (WT: open arms= 14.83 ± 1.079, closed arms= 4.750 ± 0.641, N= 12; Sidak’s multiple comparisons test, ****p < 0.0001; R451C-NL3: open arms= 15.00 ± 0.683, closed arms= 7.0 ± 1.358, N= 10; Sidak’s multiple comparisons test, ****p = 0.0001; one-way ANOVA F= 30.33, ****p < 0.0001). (F2) Latency to enter the OA (WT= 61.0 ± 20.04 s, N= 12; R451C-NL3= 43 ± 21.02 s, N= 10; Mann-Whitney test, p = 0.507). Each dot represents a single measurement. Mean ± SEM of data is reported. suppl.figure2.tif Supplementary Figure 2. Top. Representative Western blot of (A) mGlu5 receptor and (B) PSD95 protein expression levels in cortical lysates of WT and KI mice. Bottom. Histograms reporting single measurements (dots), and mean ± SEM of data. (A) WT: 1.00 ± 0.037, n = 9, R451C-NL3: 0.968 ± 0.086, n = 7, unpaired t-test: p = 0.688; (B) WT: 1.00 ± 0.258, n = 6, R451C-NL3: 0.869 ± 0.184, n = 5, unpaired t-test: p = 0.702. C,D,E) Western blot analysis of (C) mGlu5 receptor, (D) mGlu1 receptor and (E) Homer protein expression levels in cortical synaptosomal preparation from KI and WT mice. Bottom. The histograms report single measurements (dots), and mean ± SEM of data. Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4893764","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":354559736,"identity":"92a02941-7958-4f17-83ea-b4989a6b1064","order_by":0,"name":"Maria Meringolo","email":"","orcid":"","institution":"IRCCS Fondazione Santa Lucia","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Meringolo","suffix":""},{"id":354559737,"identity":"26687084-39e3-41e3-a2e5-2b2d8b2c1510","order_by":1,"name":"Martina Montanari","email":"","orcid":"","institution":"IRCCS Fondazione Santa 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04:53:29","currentVersionCode":2,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-4893764/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-4893764/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":73911263,"identity":"ef693702-7712-412f-9caa-e51808a7a114","added_by":"auto","created_at":"2025-01-15 22:46:20","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4168938,"visible":true,"origin":"","legend":"","description":"","filename":"NLGN3mGlu5final.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4893764/v2_covered_a97507e5-a9d2-4db8-8d7f-43b6029bf0a0.pdf"},{"id":73910862,"identity":"5a4ed332-9674-40c3-84df-91f149bd586b","added_by":"auto","created_at":"2025-01-15 22:30:10","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":28573038,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 1. \u003c/strong\u003eSocial behaviors: (Top) Cartoon of the 3-chamber apparatus in the two phases of the test. A1) Amount of time spent interacting with the social stimulus (SOC) or non-social stimulus (OBJ) in WT versus R451C-NL3 mice \u003cstrong\u003e(\u003c/strong\u003eInteraction time: WT\u003csub\u003eobject\u003c/sub\u003e= 60.08 ± 6.811s, WT\u003csub\u003esocial\u003c/sub\u003e= 104.8 ± 10.81s, N= 10, Sidak’s multiple comparisons test *p = 0.018; R451C-NL3\u003csub\u003eobject\u003c/sub\u003e= 75.20 ± 10.16s; R451C-NL3\u003csub\u003esocial\u003c/sub\u003e= 80.11 ± 12.42s, N= 9, Sidak’s multiple comparisons test p = 0.9997; two-way ANOVA, F(1,34)\u003csub\u003einteraction\u003c/sub\u003e = 5.978, P = 0.448)\u003cstrong\u003e. \u003c/strong\u003eA2) Bar graph of the social preference index of control and R451C-NL3 mice (WT\u003csub\u003esocial preference index\u003c/sub\u003e= 0.633 ± 0.028, R451C-NL3\u003csub\u003esocial preference index\u003c/sub\u003e= 0.509 ± 0.038; unpaired t-test *p = 0.018).\u003cstrong\u003e \u003c/strong\u003eA3) Amount of time spent interacting with the novel stimulus (NOV) or the familiar stimulus (FAM) in the novelty phase of the test (Interaction time: WT\u003csub\u003efamiliar\u003c/sub\u003e = 60.79 ± 7.317s, WT\u003csub\u003enovel\u003c/sub\u003e= 104.5 ± 15.46s, N= 10, Sidak’s multiple comparisons test, *p = 0.037; R451C-NL3\u003csub\u003efamiliar\u003c/sub\u003e= 76.54 ± 8.005s;\u0026nbsp; R451C-NL3\u003csub\u003enovel\u003c/sub\u003e= 52.41 ± 10.12s, N= 9, Sidak’s multiple comparisons test, p = 0.586; two-way ANOVA, F(1,34)\u003csub\u003einteraction\u003c/sub\u003e = 9.670, **p = 0.0038).\u003cstrong\u003e\u0026nbsp; \u003c/strong\u003eA4) Bar graph of the novel preference index of WT and R451C-NL3 mice \u003cstrong\u003e(\u003c/strong\u003eWT\u003csub\u003enovel preference index\u003c/sub\u003e= 0.615 ± 0.049, R451C-NL3\u003csub\u003enovel preference index\u003c/sub\u003e= 0.400 ± 0.056; Mann-Whitney test *p = 0.017).\u003cstrong\u003e \u003c/strong\u003eAnhedonia: (Top) Cartoon of the sucrose splash test.\u003cstrong\u003e \u003c/strong\u003eB1) Number of dorsal self-grooming\u003cstrong\u003e (\u003c/strong\u003eWT= 10.42 ± 0.857, N= 12; R451C-NL3= 7.8 ± 0.841, N= 10; unpaired t-test *p = 0.043) and (B2) latency to the first grooming of R451C-NL3 mice and their WT littermates (WT= 38.75 ± 7.072 s, N= 12; R451C-NL3= 41.70 ± 6.414 s, N= 10; unpaired t-test p = 0.765).\u003cstrong\u003e \u003c/strong\u003e\u003cu\u003eCognitive function:\u003c/u\u003e\u003cstrong\u003e \u003c/strong\u003eC) Novel object recognition test (NORT). (C1) Summary plots depicting the amount of time spent interacting with the familiar (FAM) or the novel (NOV) object during the test session (WT\u003csub\u003efamiliar\u003c/sub\u003e= 13.78 ± 1.286 s, WT\u003csub\u003enovel\u003c/sub\u003e= 24.56 ± 2.235 s, N= 12; Sidak’s multiple comparisons test, **p = 0.003; R451C-NL3\u003csub\u003efamiliar\u003c/sub\u003e= 16.54 ± 2.124 s;\u0026nbsp; R451C-NL3\u003csub\u003enovel\u003c/sub\u003e= 29.91 ± 2.660 s, N= 10; Sidak’s multiple comparisons test, ***p = 0.0006; one-way ANOVA, F= 12.29, ****p \u0026lt; 0.0001). (C2) Bar chart reporting the discrimination index for the novel object (WT= 0.265 ± 0.048, N= 12; R451C-NL3= 0.298 ± 0.056, N= 10; unpaired t-test p = 0.655). D) Y maze test. The summary plots report (D1) the percentage of spontaneous alternations (WT= 59.32 ± 2.666 %, N= 12; R451C-NL3= 53.80 ± 2.613 %, N= 10; unpaired t-test p = 0.159), and (D2) the total number of entries in the three arms of the Y maze apparatus (WT= 49.83 ± 2.719, N= 12; R451C-NL3= 63.00 ± 3.836, N= 10; unpaired t-test **p = 0.009). \u003cu\u003eAnxiety behaviors:\u003c/u\u003e E) Open field test. (E1) Bar charts reporting the time spent in the center of the arena (WT= 222.7 ± 22.92 s, N= 12; R451C-NL3= 260.8 ± 25.21 s, N= 10; unpaired t-test p = 0.276), (E2) number of entries in the center zone (WT= 46.25 ± 4.799, N= 12; R451C-NL3= 59.20 ± 5.974, N= 10; unpaired t-test p = 0.103) and (E3) number of defecations during the session (WT= 6.0 ± 0.835, N= 12; R451C-NL3= 7.7 ± 0.731, N= 10; unpaired t-test p = 0.149). F) Elevated plus maze (EPM). (F1) Summary plots comparing the number of entries of mice in the open (OA) \u003cem\u003evs.\u003c/em\u003e the closed arms (CA) (WT: open arms= 14.83 ± 1.079, closed arms= 4.750 ± 0.641, N= 12; Sidak’s multiple comparisons test, ****p \u0026lt; 0.0001; R451C-NL3: open arms= 15.00 ± 0.683, closed arms= 7.0 ± 1.358, N= 10; Sidak’s multiple comparisons test, ****p = 0.0001; one-way ANOVA F= 30.33, ****p \u0026lt; 0.0001). (F2) Latency to enter the OA (WT= 61.0 ± 20.04 s, N= 12; R451C-NL3= 43 ± 21.02 s, N= 10; Mann-Whitney test, p = 0.507). Each dot represents a single measurement. Mean ± SEM of data is reported.\u003c/p\u003e","description":"","filename":"suppl.figure1.tif","url":"https://assets-eu.researchsquare.com/files/rs-4893764/v2/74158bbc98d3fdcd0c91b962.tif"},{"id":73910861,"identity":"458d9915-471a-4d5e-b90b-5c39e48f6889","added_by":"auto","created_at":"2025-01-15 22:30:10","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":25674310,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 2. \u003c/strong\u003eTop. Representative Western blot of (A) mGlu5 receptor and (B) PSD95 protein expression levels in cortical lysates of WT and KI mice. Bottom. Histograms reporting single measurements (dots), and mean ± SEM of data. (A) WT: 1.00 ± 0.037, n = 9, R451C-NL3: 0.968 ± 0.086, n = 7, unpaired t-test: p = 0.688; (B) WT: 1.00 ± 0.258, n = 6, R451C-NL3: 0.869 ± 0.184, n = 5, unpaired t-test: p = 0.702. C,D,E) Western blot analysis of (C) mGlu5 receptor, (D) mGlu1 receptor and (E) Homer protein expression levels in cortical synaptosomal preparation from KI and WT mice. Bottom. The histograms report single measurements (dots), and mean ± SEM of data.\u003c/p\u003e","description":"","filename":"suppl.figure2.tif","url":"https://assets-eu.researchsquare.com/files/rs-4893764/v2/fdd65d378ddd9fc6597d2384.tif"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"Impaired metabotropic glutamate type 5 receptor signaling in the dorsal striatum of the R451C-neuroligin 3 mouse model of Autism Spectrum Disorder","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"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":"Behavior, proteomics, electrophysiology, glutamate metabotropic receptors, corticostriatal synapses","lastPublishedDoi":"10.21203/rs.3.rs-4893764/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4893764/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHuman genetics indicates enrichment of synaptic pathway-related mutations in Autism Spectrum Disorder (ASD). Accordingly, several preclinical studies have reported synaptic alterations in different brain areas of relevant ASD mouse models. In particular, we previously showed that corticostriatal long-term synaptic depression is impaired in the dorsal striatum of mice carrying the ASD-associated R451C mutation in the NL3 gene, coding for the postsynaptic protein neuroligin 3. Here, we used behavioral, proteomic, biochemical, and electrophysiological approaches to explore the dorsal striatum-dependent functions in the R451C-NL3 knock-in mouse model of ASD.\u003c/p\u003e\n\u003cp\u003eA detailed behavioral analysis confirmed striatum-dependent alterations in these mice. We further explored the synaptic function in the dorsal striatum, disclosing modifications of the glutamatergic postsynaptic density protein composition and the impairment of different forms of corticostriatal long-term synaptic plasticity involving the activation of group I metabotropic glutamate receptors, namely activity-dependent depression and potentiation, and pharmacological 3,5-DHPG-induced synaptic depression. Notably, activation of group I metabotropic glutamate receptors was not able to potentiate NMDA receptor-mediated currents. Protein expression levels of type 5 metabotropic glutamate receptor were reduced at striatal synapses, whereas the protein level and function of glutamate ionotropic receptors were unaltered. Overall, our findings point to a significant impairment of metabotropic glutamate receptor type 5 signaling in neuroligin 3 knock-in mice, affecting the dorsal striatum circuitry, that has been implicated in several autism-related behaviors.\u003c/p\u003e","manuscriptTitle":"Impaired metabotropic glutamate type 5 receptor signaling in the dorsal striatum of the R451C-neuroligin 3 mouse model of Autism Spectrum Disorder","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2025-01-15 22:30:05","doi":"10.21203/rs.3.rs-4893764/v2","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}},{"code":1,"date":"2024-09-16 09:10:15","doi":"10.21203/rs.3.rs-4893764/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":"41f8af2f-ae1f-43fa-be57-01a4ed93c4bc","owner":[],"postedDate":"January 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-01-18T13:23:14+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-15 22:30:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-4893764","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4893764","identity":"rs-4893764","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}