Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder

Genes Brain Behav. 2018 Jan;17(1):4-22. doi: 10.1111/gbb.12405. Epub 2017 Sep 5.

Abstract

To expand, analyze and extend published behavioral phenotypes relevant to autism spectrum disorder (ASD), we present a study of three ASD genetic mouse models: Feng's Shank3tm2Gfng model, hereafter Shank3/F, Jiang's Shank3tm1Yhj model, hereafter Shank3/J and the Cacna1c deletion model. The Shank3 models mimick gene mutations associated with Phelan-McDermid Syndrome and the Cacna1c model recapitulates the deletion underlying Timothy syndrome. This study utilizes both standard and novel behavioral tests with the same methodology used in our previously published companion report on the Cntnap2 null and 16p11.2 deletion models. We found that some but not all behaviors replicated published findings and those that did replicate, such as social behavior and overgrooming in Shank3 models, tended to be milder than reported elsewhere. The Shank3/F model, and to a much lesser extent, the Shank3/J and Cacna1c models, showed hypoactivity and a general anxiety-like behavior triggered by external stimuli which pervaded social interactions. We did not detect deficits in a cognitive procedural learning test nor did we observe perseverative behavior in these models. We did, however, find differences in exploratory patterns of Cacna1c mutant mice suggestive of a behavioral effect in a social setting. In addition, only Shank3/F showed differences in sensory-gating. Both positive and negative results from this study will be useful in identifying the most robust and replicable behavioral signatures within and across mouse models of autism. Understanding these phenotypes may shed light of which features to study when screening compounds for potential therapeutic interventions.

Keywords: Autism; Cacna1c; Phelan-McDermid syndrome; Shank3; Timothy syndrome; behavior; development; mouse genetic models; phenotyping; replication.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anxiety / genetics
  • Anxiety / metabolism
  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / metabolism
  • Autistic Disorder / genetics
  • Behavior, Animal / physiology
  • Calcium Channels, L-Type / genetics*
  • Calcium Channels, L-Type / metabolism
  • Chromosome Deletion
  • Chromosome Disorders / genetics
  • Chromosomes, Human, Pair 22 / genetics
  • Disease Models, Animal*
  • Female
  • Long QT Syndrome / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Social Behavior
  • Syndactyly / genetics

Substances

  • CACNA1C protein, mouse
  • Calcium Channels, L-Type
  • Nerve Tissue Proteins
  • Shank3 protein, mouse

Supplementary concepts

  • Telomeric 22q13 Monosomy Syndrome
  • Timothy syndrome