Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

Nature. 2011 Apr 28;472(7344):437-42. doi: 10.1038/nature09965. Epub 2011 Mar 20.

Abstract

Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan-McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice.

Publication types

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

MeSH terms

  • Animals
  • Autistic Disorder / genetics*
  • Autistic Disorder / physiopathology*
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Compulsive Behavior / genetics
  • Female
  • Gene Deletion
  • Grooming
  • Male
  • Mice
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Neostriatum / pathology
  • Neostriatum / physiopathology*
  • Nerve Tissue Proteins
  • Neural Pathways
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Self-Injurious Behavior / genetics
  • Self-Injurious Behavior / physiopathology
  • Social Behavior
  • Synapses / metabolism
  • Synapses / pathology

Substances

  • Carrier Proteins
  • Mutant Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Shank3 protein, mouse