Behavioural Phenotypes and Neural Circuit Dysfunctions in Mouse Models of Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition primarily characterised by alterations in social interaction and communication combined with the presence of restricted interests and stereotyped behaviours. Mutations in several genes have been associated with ASD resulting in the generation of corresponding mouse models. Here, we focus on the behavioural (social and stereotyped behaviours), functional and structural traits of mice with mutations in genes encoding defined synaptic proteins including adhesion proteins, scaffolding proteins and subunits of channels and receptors. A meta-analysis on ASD mouse models shows that they can be divided into two subgroups. Cluster I gathered models highly impaired in social interest, stereotyped behaviours, synaptic physiology and protein composition, while Cluster II regrouped much less impaired models, with typical social interactions. This distribution was not related to gene families. Even within the large panel of mouse models carrying mutations in Shank3, the number of mutated isoforms was not related to the severity of the phenotype. Our study points that the majority of structural or functional analyses were performed in the hippocampus. However, to robustly link the structural and functional impairments with the behavioural deficits observed, brain structures forming relevant nodes in networks involved in social and stereotyped behaviours should be targeted in the future. In addition, the characterisation of core ASD-like behaviours needs to be more detailed using new approaches quantifying the variations in social motivation, recognition and stereotyped behaviours.

Shank2 Mutant Mice Display Hyperactivity Insensitive to Methylphenidate and Reduced Flexibility in Social Motivation, but Normal Social Recognition

“…Many mouse models of autism display only subtle abnormalities in classical behavioral tests for social interest (reviewed in Ferhat et al, 2017 ). One hypothesis is that the main social problem might reside in the social reward system, which can impair behavioral flexibility [see for instance the lack of social modulation of ultrasonic vocalizations in Shank1 mutant mice ( Wöhr et al, 2011 )].…”

Proteomic Analysis of Brain Region and Sex-Specific Synaptic Protein Expression in the Adult Mouse Brain

“…These so-called synaptopathies include complex disorders such as intellectual disability, schizophrenia and autism spectrum disorder (ASD) [25][26][27][28][29]. Animal mutant models of synaptopathies can mimic core aspects of the human diseases [30][31][32]. Despite all limitations, these models provide crucial information for the understanding of the biological pathways involved in the development of neuropsychiatric disorders.…”

SHANK3 Downregulation in the Ventral Tegmental Area Accelerates the Extinction of Contextual Associations Induced by Juvenile Non-familiar Conspecific Interaction

“…Considering the association between ASD and SHANK3 mutations in humans, several Shank3 mutant mouse lines have been generated to study both the contribution of the gene to the emergence of ASD-related symptoms and the neuronal circuit dysfunctions underlying aberrant behavioral traits. Sociability, social preference and social novelty recognition abnormalities have been observed with variable severity in mutant mice lacking the different SHANK3 isoforms (Ferhat et al, 2017 ). Besides its role in controlling sociability and stereotypes in mice, the expression of certain SHANK3 variants is necessary for appropriate learning.…”