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

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 Shank3 model, hereafter Shank3/F, Jiang's Shank3 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.

Sex‐dependent effects of Cacna1c haploinsufficiency on juvenile social play behavior and pro‐social 50‐kHz ultrasonic communication in rats

“…6,7 Furthermore, SHANK scaffolding proteins, strongly associated with ASD, 87 have been implicated in the regulation of voltage-gated L-type Ca 2+ channels, and thus mutations in the SHANK gene family could lead to Ca v 1.2 malfunctioning, 88 possibly contributing to ASD-related behavioral phenotypes. In fact, a G406R TS mouse model was reported to completely recapitulate an ASD-related behavioral phenotype and was characterized by lack of sociability, together with increased marble-burying behavior, impaired reversal learning abilities, and altered emission of isolation-induced ultrasonic calling in pups, 89 [89][90][91][92][93][94] This is particularly surprising because available evidence in humans points toward stronger effects in women than in men. 12,39,40 Moreover, the role of Cacna1c in regulating relevant behavioral phenotypes during the critical developmental period of adolescence, which is characterized by a particularly rich social behavior repertoire including social play behavior, [47][48][49] has not been extensively studied.…”

Developmental social communication deficits in the Shank3 rat model of phelan‐mcdermid syndrome and autism spectrum disorder

“…(2) social deficits were detected in Shank3 2/2 male mice in dyad interactions, but no deficits were observed in the three-chambered assay [Dhamne et al, 2017]; and (3) an independent inter-laboratory study failed to replicate three-chambered social approach deficits in two Shank3 mutant models [Kabitzke et al, 2017].…”

Explorations and perspectives on the neurobiological bases of autism spectrum disorder

“…The first is to engineer mice with mutations in specific genes or copy‐number variants (CNVs), based on rare mutations that are known to give rise to so‐called syndromic cases of ASD in the human population (Ehlinger & Commons, ; Liska et al ., ), or based on data from the large genomewide association (GWAS) studies where more common single nucleotide polymorphisms (SNPs) have been associated with increased risk for an ASD (Autism Spectrum Disorders Working Group of The Psychiatric Genomics, ). Even in models of known ‘syndromic’ mutations, the phenotypes of the animals can be relatively mild (Kabitzke et al ., ) and difficult to relate to the human condition.…”