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

Rebeca Mejias; Shu-Ling Chiu; Mei Han; Rebecca Rose; Ana Gil-Infante; Yifan Zhao; Richard L. Huganir; Tao Wang

Neurobiology of Disease (Dec 2019)

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

Rebeca Mejias,
Shu-Ling Chiu,
Mei Han,
Rebecca Rose,
Ana Gil-Infante,
Yifan Zhao,
Richard L. Huganir,
Tao Wang

Affiliations

Rebeca Mejias: McKusick-Nathans Department of Genetic Medicine and Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Physiology, University of Seville, 41012 Seville, Spain; Corresponding author at: Department of Physiology, School of Biology, University of Seville, Avenida de la Reina Mercedes s/n, 41012 Sevilla, Spain.
Shu-Ling Chiu: Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA
Mei Han: McKusick-Nathans Department of Genetic Medicine and Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21205, USA
Rebecca Rose: McKusick-Nathans Department of Genetic Medicine and Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21205, USA
Ana Gil-Infante: Department of Physiology, University of Seville, 41012 Seville, Spain
Yifan Zhao: McKusick-Nathans Department of Genetic Medicine and Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21205, USA
Richard L. Huganir: Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA
Tao Wang: McKusick-Nathans Department of Genetic Medicine and Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21205, USA; Corresponding author at: McKusick-Nathans Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University School of Medicine, 733 North Broadway BRB 513, Baltimore, MD 21205, USA.

Journal volume & issue: Vol. 132

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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