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

Neurobiol Dis. 2019 Dec:132:104602. doi: 10.1016/j.nbd.2019.104602. Epub 2019 Aug 30.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency*
  • Animals
  • Autistic Disorder / metabolism
  • Excitatory Postsynaptic Potentials / physiology
  • Grooming / physiology*
  • Intracellular Signaling Peptides and Proteins / deficiency*
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / deficiency*
  • Protein Transport / physiology
  • Purkinje Cells / metabolism*
  • Receptor, Metabotropic Glutamate 5 / metabolism*
  • Receptors, AMPA / metabolism
  • Signal Transduction / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • Grip1 protein, mouse
  • Grip2 protein, mouse
  • Grm5 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Receptor, Metabotropic Glutamate 5
  • Receptors, AMPA