Autism-Associated Insertion Mutation (InsG) of Shank3 Exon 21 Causes Impaired Synaptic Transmission and Behavioral Deficits

J Neurosci. 2015 Jul 1;35(26):9648-65. doi: 10.1523/JNEUROSCI.3125-14.2015.

Abstract

SHANK3 (also known as PROSAP2) is a postsynaptic scaffolding protein at excitatory synapses in which mutations and deletions have been implicated in patients with idiopathic autism, Phelan-McDermid (aka 22q13 microdeletion) syndrome, and other neuropsychiatric disorders. In this study, we have created a novel mouse model of human autism caused by the insertion of a single guanine nucleotide into exon 21 (Shank3(G)). The resulting frameshift causes a premature STOP codon and loss of major higher molecular weight Shank3 isoforms at the synapse. Shank3(G/G) mice exhibit deficits in hippocampus-dependent spatial learning, impaired motor coordination, altered response to novelty, and sensory processing deficits. At the cellular level, Shank3(G/G) mice also exhibit impaired hippocampal excitatory transmission and plasticity as well as changes in baseline NMDA receptor-mediated synaptic responses. This work identifies clear alterations in synaptic function and behavior in a novel, genetically accurate mouse model of autism mimicking an autism-associated insertion mutation. Furthermore, these findings lay the foundation for future studies aimed to validate and study region-selective and temporally selective genetic reversal studies in the Shank3(G/G) mouse that was engineered with such future experiments in mind.

Keywords: Phelan–McDermid syndrome; Shank3; autism; behavior; postsynaptic density; synaptic plasticity.

Publication types

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

MeSH terms

  • Animals
  • Disease Models, Animal
  • Excitatory Postsynaptic Potentials / genetics
  • Exons / genetics*
  • Exploratory Behavior / physiology
  • Female
  • Grooming / physiology
  • Hippocampus / cytology
  • Locomotion / genetics
  • Male
  • Maze Learning / physiology
  • Mental Disorders / genetics*
  • Mice
  • Mice, Transgenic
  • Microfilament Proteins
  • Mutagenesis, Insertional / methods*
  • Mutation / genetics*
  • N-Methylaspartate / pharmacology
  • Nerve Tissue Proteins / genetics*
  • Nesting Behavior / physiology
  • Sodium Channel Blockers / pharmacology
  • Synaptic Transmission / genetics*
  • Tetrodotoxin / pharmacology

Substances

  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Shank3 protein, mouse
  • Sodium Channel Blockers
  • Tetrodotoxin
  • N-Methylaspartate