Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects

Neuron. 2016 Jan 6;89(1):147-62. doi: 10.1016/j.neuron.2015.11.023. Epub 2015 Dec 10.

Abstract

Genetic studies have revealed significant overlaps of risk genes among psychiatric disorders. However, it is not clear how different mutations of the same gene contribute to different disorders. We characterized two lines of mutant mice with Shank3 mutations linked to ASD and schizophrenia. We found both shared and distinct synaptic and behavioral phenotypes. Mice with the ASD-linked InsG3680 mutation manifest striatal synaptic transmission defects before weaning age and impaired juvenile social interaction, coinciding with the early onset of ASD symptoms. On the other hand, adult mice carrying the schizophrenia-linked R1117X mutation show profound synaptic defects in prefrontal cortex and social dominance behavior. Furthermore, we found differential Shank3 mRNA stability and SHANK1/2 upregulation in these two lines. These data demonstrate that different alleles of the same gene may have distinct phenotypes at molecular, synaptic, and circuit levels in mice, which may inform exploration of these relationships in human patients.

Publication types

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

MeSH terms

  • Aging
  • Animals
  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / metabolism
  • Behavior, Animal
  • Disease Models, Animal
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Mice, Transgenic
  • Microfilament Proteins
  • Mutation / genetics*
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism*
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism
  • Social Behavior*
  • Synaptic Transmission / genetics*

Substances

  • Microfilament Proteins
  • Nerve Tissue Proteins
  • SHANK1 protein, mouse
  • Shank2 protein, mouse
  • Shank3 protein, mouse