The Genetics of Social Behavior in Mice: Implications for Autism Spectrum Disorders

Background: Varying in presentation and severity of symptoms, autism spectrum disorders (ASD) are likely influenced by a combination of genetic and environmental factors. Despite decades of research and evidence of a strong genetic component, to date little is known about their etiology. As with Huntington's, schizophrenia and Alzheimer's, mouse models may play a critical role in helping us understand the etiology of ASD and develop more effective therapies. Through careful behavioral analyses most of the core characteristics of ASD (i.e., impairments in social interaction, restlessness and distraction, difficulty with language, repetitive and stereotyped motor behaviors) can be modeled in mice. One of the defining characteristics of ASD, impaired social interaction, can be easily studied in mice. Some inbred strains (e.g., BTBR T+ tf/J (BTBR), A/J, BALB/cBy) display lowered sociability compared to others (e.g., C57BL/6J (B6), FVB/NJ (FVB)) and thus are selected for further genetic analysis.

Objectives: Our laboratory is investigating the role of genetics in impaired social behavior in A/J and BTBR inbred strains. The objective of our current research is to examine the role of genetics in sociability in mice. Ultimately, we want to understand the biology of social behavior and how we can develop appropriate therapeutic interventions for ASD.

Methods: We measured sociability through a social approach assay. In one study we examined social behavior in a set of chromosome substitution strains developed by crossing B6 and A/J. The effects of each chromosome from the A/J strain are studied in isolation, while maintaining the remainder of the genetic background as B6. Although these strains do not reveal individual genes, they do implicate the gene set from specific chromosomes, which can then be studied further by microarray and recombinant analyses. We also examined these strains in anxiety and activity assays (open field, zero maze). This way we can separate genetic regions unique to sociability from those related to activity and/or anxiety. Thus, the degree to which activity and anxiety contribute to social behavior is assayed. In another series of studies, we generated a small F2 population between BTBR and FVB strains and examined sociability and neuroanatomy. This study examines both the genetics of social behavior and related neurobiological markers.

Results: The consomic study indicates that a large number of chromosomes are involved in social behavior in mice. Some of these chromosomes are also involved in activity and anxiety-related behaviors. However, a few chromosomes appear to be uniquely involved in social behavior. The behavioral analyses of the F2 mice illustrate a wider range of sociability in this population than in either of the parental strains, as well as, a small but significant correlation between sociability and corpus callosum size. Additional genetic and neuroanatomical analyses are ongoing.

Conclusions: Inbred strains of mice are an important tool for elucidating the genetics underlying impairments in social interaction. Our studies illustrate that many genetic regions are linked to social behavior in mice. These regions must be studied in more detail to establish specific genes involved in social behavior and ultimately ASD.