Spinophilin Limits Metabotropic Glutamate Receptor 5 Scaffolding to the Postsynaptic Density and Cell Type Specifically Mediates Excessive Grooming

dc.contributor.authorMorris, Cameron W.
dc.contributor.authorWatkins, Darryl S.
dc.contributor.authorShah, Nikhil R.
dc.contributor.authorPennington, Taylor
dc.contributor.authorHens, Basant
dc.contributor.authorQi, Guihong
dc.contributor.authorDoud, Emma H.
dc.contributor.authorMosley, Amber L.
dc.contributor.authorAtwood, Brady K.
dc.contributor.authorBaucum, Anthony J., II
dc.contributor.departmentPharmacology and Toxicology, School of Medicine
dc.date.accessioned2024-08-23T09:20:24Z
dc.date.available2024-08-23T09:20:24Z
dc.date.issued2023
dc.description.abstractBackground: Grooming dysfunction is a hallmark of the obsessive-compulsive spectrum disorder trichotillomania. Numerous preclinical studies have utilized SAPAP3-deficient mice for understanding the neurobiology of repetitive grooming, suggesting that excessive grooming is caused by increased metabotropic glutamate receptor 5 (mGluR5) activity in striatal direct- and indirect-pathway medium spiny neurons (MSNs). However, the MSN subtype-specific signaling mechanisms that mediate mGluR5-dependent adaptations underlying excessive grooming are not fully understood. Here, we investigated the MSN subtype-specific roles of the striatal signaling hub protein spinophilin in mediating repetitive motor dysfunction associated with mGluR5 function. Methods: Quantitative proteomics and immunoblotting were utilized to identify how spinophilin impacts mGluR5 phosphorylation and protein interaction changes. Plasticity and repetitive motor dysfunction associated with mGluR5 action were measured using our novel conditional spinophilin mouse model in which spinophilin was knocked out from striatal direct-pathway MSNs and/or indirect-pathway MSNs. Results: Loss of spinophilin only in indirect-pathway MSNs decreased performance of a novel motor repertoire, but loss of spinophilin in either MSN subtype abrogated striatal plasticity associated with mGluR5 function and prevented excessive grooming caused by SAPAP3 knockout mice or treatment with the mGluR5-specific positive allosteric modulator VU0360172 without impacting locomotion-relevant behavior. Biochemically, we determined that the spinophilin-mGluR5 interaction correlates with grooming behavior and that loss of spinophilin shifts mGluR5 interactions from lipid raft-associated proteins toward postsynaptic density proteins implicated in psychiatric disorders. Conclusions: These results identify spinophilin as a novel striatal signaling hub molecule in MSNs that cell subtype specifically mediates behavioral, functional, and molecular adaptations associated with repetitive motor dysfunction in psychiatric disorders.
dc.eprint.versionAuthor's manuscript
dc.identifier.citationMorris CW, Watkins DS, Shah NR, et al. Spinophilin Limits Metabotropic Glutamate Receptor 5 Scaffolding to the Postsynaptic Density and Cell Type Specifically Mediates Excessive Grooming. Biol Psychiatry. 2023;93(11):976-988. doi:10.1016/j.biopsych.2022.12.008
dc.identifier.urihttps://hdl.handle.net/1805/42898
dc.language.isoen_US
dc.publisherElsevier
dc.relation.isversionof10.1016/j.biopsych.2022.12.008
dc.relation.journalBiological Psychiatry
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectSignaling
dc.subjectPhosphatase targeting proteins
dc.subjectPostsynaptic density
dc.subjectPlasticity
dc.subjectStriatum
dc.subjectTrichotillomania
dc.titleSpinophilin Limits Metabotropic Glutamate Receptor 5 Scaffolding to the Postsynaptic Density and Cell Type Specifically Mediates Excessive Grooming
dc.typeArticle
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