Phenotypic Consequences of Misregulation of Human Chromosome 15-Associated Autism Candidate Genes in Mouse

Background: Multiple lines of evidence implicate genes within human chromosome 15q11-q13 as contributing to autism spectrum disorders, including regional duplication occurring in approximately 2% of patients with non-syndromic autism, positive linkage association in patient populations with idiopathic autism, and aberrant gene expression levels in both these groups and in patients with the autism spectrum disorder, Rett syndrome. The consequences of misexpression of these genes individually or collectively at the cellular and organismal level is not known.

Objectives: To determine the behavioral and neurologic consequences of misexpression of individual human chromosome 15-associated autism candidate genes in mouse.

Methods: Several mouse lines have been generated that over- or under-express candidate genes utilizing ptet-Off inducible expression vectors constructs or shRNA-mediated gene knockdown. Behavioral phenotypes were assessed in these, heterozygous gene knockout and wild-type control animals using standard protocols, including anxiety (open field), exploratory (place preference & T-maze), socialization (interest, preference & memory: tethered & free interactions) and reversal learning (radial maze).

Results: No changes have been observed to date in anxiety, exploratory or general social interest in our lines, with the exception of rare individual animals exhibiting an overall decrease in activity levels or premature death in adulthood. Preliminary data suggests that misexpression of separate candidate genes leads to abnormal trends in place-preference (p<0.002) or T-maze behaviors (p<0.06), respectively. We are currently following up these studies to more specifically define abnormal behaviors, and define their relationship to total or regional gene expression levels.

Conclusions: We provide evidence that small changes in the expression of murine genes homologous to autism candidate genes within human 15q11-q13 affect phenotypes in mouse believed to be representative of autism diagnostic criteria in humans, including social and perseverative behaviors. Aberrant expression of these genes together or individually may contribute to the development of autism spectrum disorder or of specific ASD-related features in patients.