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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number104602
JournalNeurobiology of Disease
Volume132
DOIs
StatePublished - Dec 1 2019

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Receptor-Interacting Protein Serine-Threonine Kinases
Grooming
Purkinje Cells
Glutamate Receptors
Knockout Mice
Cerebellum
Autistic Disorder
AMPA Receptors
Electrophysiology
Interpersonal Relations
Synapses
Walking
Rodentia
Anxiety
Phosphorylation

Keywords

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

ASJC Scopus subject areas

  • Neurology

Cite this

Purkinje cell-specific Grip1/2 knockout mice show increased repetitive self-grooming and enhanced mGluR5 signaling in cerebellum. / Mejias, Rebeca; Chiu, Shu-Ling; Han, Mei; Rose, Rebecca; Gil-Infante, Ana; Zhao, Yifan; Huganir, Richard L; Wang, Tao.

In: Neurobiology of Disease, Vol. 132, 104602, 01.12.2019.

Research output: Contribution to journalArticle

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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.",
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