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Neurobiol Dis. 2019 Aug 30;132:104602. doi: 10.1016/j.nbd.2019.104602. [Epub ahead of print]

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

Author information

1
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. Electronic address: rmejias@us.es.
2
Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA.
3
McKusick-Nathans Department of Genetic Medicine and Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21205, USA.
4
Department of Physiology, University of Seville, 41012 Seville, Spain.
5
McKusick-Nathans Department of Genetic Medicine and Department of Pediatrics, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: twang9@jhmi.edu.

Abstract

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.

KEYWORDS:

AMPA receptors; Autism; Cerebellum; Glutamate signaling; Grip1/2; Grooming; LTD; Purkinje cells; mGluR receptors

PMID:
31476380
DOI:
10.1016/j.nbd.2019.104602

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