Purkinje cell-specific Grip1/2 knockout mice show increased repetitive self-grooming and enhanced mGluR5 signaling in cerebellum

Cerebellar Purkinje cell (PC) loss is a consistent pathological finding in autism. However, neural mechanisms of PC-dysfunction in autism remain poorly characterized. Glutamate receptor interacting proteins 1/2 (Grip1/2) regulate AMPA receptor (AMPAR) trafficking and synaptic strength. To evaluate r...

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Autores: Mejías Estévez, Rebeca María, Chiu, Shu-Ling, Rose, Rebecca, Gil Infante, Ana, Zhao, Yifan, Wang, Tao, Huganir, Richard L
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/94035
Acceso en línea:https://hdl.handle.net/11441/94035
https://doi.org/10.1016/j.nbd.2019.104602
Access Level:acceso abierto
Palabra clave:AMPA receptors
Autism
Cerebellum
Glutamate signaling
Grip1/2
Grooming
LTD
Purkinje cells
mGluR receptors
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spelling Purkinje cell-specific Grip1/2 knockout mice show increased repetitive self-grooming and enhanced mGluR5 signaling in cerebellumMejías Estévez, Rebeca MaríaChiu, Shu-LingRose, RebeccaGil Infante, AnaZhao, YifanWang, TaoHuganir, Richard LAMPA receptorsAutismCerebellumGlutamate signalingGrip1/2GroomingLTDPurkinje cellsmGluR receptorsCerebellar Purkinje cell (PC) loss is a consistent pathological finding in autism. However, neural mechanisms of PC-dysfunction in autism remain poorly characterized. Glutamate receptor interacting proteins 1/2 (Grip1/2) regulate AMPA receptor (AMPAR) trafficking and synaptic strength. To evaluate role of PC-AMPAR signaling in autism, we produced PC-specific Grip1/2 knockout mice by crossing Grip2 conventional and Grip1 conditional KO with L7-Cre driver mice. PCs in the mutant mice showed normal morphology and number, and a lack of Grip1/2 expression. Rodent behavioral testing identified normal ambulation, anxiety, social interaction, and an increase in repetitive self-grooming. Electrophysiology studies revealed normal mEPSCs but an impaired mGluR-LTD at the Parallel Fiber-PC synapses. Immunoblots showed increased expression of mGluR5 and Arc, and enhanced phosphorylation of P38 and AKT in cerebellum of PC-specific Grip1/2 knockout mice. Results indicate that loss of Grip1/2 in PCs contributes to increased repetitive self-grooming, a core autism behavior in mice. Results support a role of AMPAR trafficking defects in PCs and disturbances of mGluR5 signaling in cerebellum in the pathogenesis of repetitive behaviors.University of Seville (V PPIT-US)Spain and an National Institute of Health (NIH) (NS085358)ElsevierFisiologíaUniversidad de SevillaNIH2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/94035https://doi.org/10.1016/j.nbd.2019.104602reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésNeurobiology of Disease, 132, 1-10.(V PPIT-US)NS085358http://dx.doi.org/10.1016/j.nbd.2019.104602info:eu-repo/semantics/openAccessoai:idus.us.es:11441/940352026-06-17T12:51:07Z
dc.title.none.fl_str_mv Purkinje cell-specific Grip1/2 knockout mice show increased repetitive self-grooming and enhanced mGluR5 signaling in cerebellum
title Purkinje cell-specific Grip1/2 knockout mice show increased repetitive self-grooming and enhanced mGluR5 signaling in cerebellum
spellingShingle Purkinje cell-specific Grip1/2 knockout mice show increased repetitive self-grooming and enhanced mGluR5 signaling in cerebellum
Mejías Estévez, Rebeca María
AMPA receptors
Autism
Cerebellum
Glutamate signaling
Grip1/2
Grooming
LTD
Purkinje cells
mGluR receptors
title_short Purkinje cell-specific Grip1/2 knockout mice show increased repetitive self-grooming and enhanced mGluR5 signaling in cerebellum
title_full Purkinje cell-specific Grip1/2 knockout mice show increased repetitive self-grooming and enhanced mGluR5 signaling in cerebellum
title_fullStr Purkinje cell-specific Grip1/2 knockout mice show increased repetitive self-grooming and enhanced mGluR5 signaling in cerebellum
title_full_unstemmed Purkinje cell-specific Grip1/2 knockout mice show increased repetitive self-grooming and enhanced mGluR5 signaling in cerebellum
title_sort Purkinje cell-specific Grip1/2 knockout mice show increased repetitive self-grooming and enhanced mGluR5 signaling in cerebellum
dc.creator.none.fl_str_mv Mejías Estévez, Rebeca María
Chiu, Shu-Ling
Rose, Rebecca
Gil Infante, Ana
Zhao, Yifan
Wang, Tao
Huganir, Richard L
author Mejías Estévez, Rebeca María
author_facet Mejías Estévez, Rebeca María
Chiu, Shu-Ling
Rose, Rebecca
Gil Infante, Ana
Zhao, Yifan
Wang, Tao
Huganir, Richard L
author_role author
author2 Chiu, Shu-Ling
Rose, Rebecca
Gil Infante, Ana
Zhao, Yifan
Wang, Tao
Huganir, Richard L
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fisiología
Universidad de Sevilla
NIH
dc.subject.none.fl_str_mv AMPA receptors
Autism
Cerebellum
Glutamate signaling
Grip1/2
Grooming
LTD
Purkinje cells
mGluR receptors
topic AMPA receptors
Autism
Cerebellum
Glutamate signaling
Grip1/2
Grooming
LTD
Purkinje cells
mGluR receptors
description Cerebellar Purkinje cell (PC) loss is a consistent pathological finding in autism. However, neural mechanisms of PC-dysfunction in autism remain poorly characterized. Glutamate receptor interacting proteins 1/2 (Grip1/2) regulate AMPA receptor (AMPAR) trafficking and synaptic strength. To evaluate role of PC-AMPAR signaling in autism, we produced PC-specific Grip1/2 knockout mice by crossing Grip2 conventional and Grip1 conditional KO with L7-Cre driver mice. PCs in the mutant mice showed normal morphology and number, and a lack of Grip1/2 expression. Rodent behavioral testing identified normal ambulation, anxiety, social interaction, and an increase in repetitive self-grooming. Electrophysiology studies revealed normal mEPSCs but an impaired mGluR-LTD at the Parallel Fiber-PC synapses. Immunoblots showed increased expression of mGluR5 and Arc, and enhanced phosphorylation of P38 and AKT in cerebellum of PC-specific Grip1/2 knockout mice. Results indicate that loss of Grip1/2 in PCs contributes to increased repetitive self-grooming, a core autism behavior in mice. Results support a role of AMPAR trafficking defects in PCs and disturbances of mGluR5 signaling in cerebellum in the pathogenesis of repetitive behaviors.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/94035
https://doi.org/10.1016/j.nbd.2019.104602
url https://hdl.handle.net/11441/94035
https://doi.org/10.1016/j.nbd.2019.104602
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Neurobiology of Disease, 132, 1-10.
(V PPIT-US)
NS085358
http://dx.doi.org/10.1016/j.nbd.2019.104602
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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