Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators

Cell Rep. 2015 Jun 9;11(9):1400-1413. doi: 10.1016/j.celrep.2015.04.064. Epub 2015 May 28.

Abstract

Haploinsufficiency of the Shank3 gene, which encodes a scaffolding protein at glutamatergic synapses, is a highly prevalent and penetrant risk factor for autism. Using combined behavioral, electrophysiological, biochemical, imaging, and molecular approaches, we find that Shank3-deficient mice exhibit autism-like social deficits and repetitive behaviors, as well as the significantly diminished NMDA receptor (NMDAR) synaptic function and synaptic distribution in prefrontal cortex. Concomitantly, Shank3-deficient mice have a marked loss of cortical actin filaments, which is associated with the reduced Rac1/PAK activity and increased activity of cofilin, the major actin depolymerizing factor. The social deficits and NMDAR hypofunction are rescued by inhibiting cofilin or activating Rac1 in Shank3-deficient mice and are induced by inhibiting PAK or Rac1 in wild-type mice. These results indicate that the aberrant regulation of synaptic actin filaments and loss of synaptic NMDARs contribute to the manifestation of autism-like phenotypes. Thus, targeting actin regulators provides a strategy for autism treatment.

Publication types

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

MeSH terms

  • Actin Depolymerizing Factors / metabolism*
  • Animals
  • Autistic Disorder / genetics
  • Autistic Disorder / metabolism*
  • Autistic Disorder / physiopathology
  • Disease Models, Animal
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neuropeptides / metabolism
  • Patch-Clamp Techniques
  • Prefrontal Cortex / physiopathology*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • p21-Activated Kinases / metabolism
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Actin Depolymerizing Factors
  • Nerve Tissue Proteins
  • Neuropeptides
  • Rac1 protein, mouse
  • Receptors, N-Methyl-D-Aspartate
  • Shank3 protein, mouse
  • p21-Activated Kinases
  • rac1 GTP-Binding Protein