Modeling of autism genetic variations in mice: Focusing on synaptic and microcircuit dysfunctions

Autism spectrum disorders (ASD) are heterogeneous neurodevelopmental disorders that are characterized by deficits in social interaction, verbal and nonverbal communication, and restrictive interests and repetitive behaviors. While human genetic studies have revealed marked heritability in ASD, it has been challenging to translate this genetic risk into a biological mechanism that influences brain development relevant to the disorder phenotypes. This is partly due to the complex genetic architecture of ASD, which involves de novo gene mutations, genomic abnormalities, and common genetic variants. Rather than trying to reconstitute the clinical disorder, using genetic model animals to examine specific features of core ASD pathophysiology offers unique opportunities for refining our understanding of neurodevelopmental mechanisms in ASD. A variety of ASD-relevant phenotypes can now be investigated in rodents, including stereotyped and repetitive behaviors, and deficits in social interaction and communication. In this review, we focus on several prevailing mouse models and discuss how studies have advanced our understanding of synaptic mechanisms that may underlie ASD pathophysiology. Although synaptic perturbations are not the only alterations relevant for ASD, we reason that understanding the synaptic underpinnings of ASD using mouse models may provide mechanistic insights into its etiology and lead to novel therapeutic and interventional strategies.