Autism spectrum disorders (ASD) are characterized by pervasive social, cognitive, language, motor and sensory processing abnormalities. How genetic and environmental factors interact on the backdrop of normal brain development to bring about these phenotypes is unclear. Cowden syndrome and macrocephaly/autism syndrome are two disorders on the autism spectrum in which affected individuals are heterozygous carriers of mutant alleles for PTEN, a repressor of PI3-kinase signaling. To develop a mouse model to investigate gene interactions underlying ASD, we are characterizing heterozygous Pten knockout mice (Pten+/-) for phenotypes relevant to ASD. At the level of behavior, we have tested these mice in a social approach assay and find that Pten+/- mice spend significantly less time interacting with a stranger mouse than do wild type mice. Furthermore, we find that Pten+/- mice have deficits in prepulse inhibition of the acoustic startle response, a measure of sensorimotor gating that is abnormal in at least some individuals with ASD. We are further characterizing these mice for neuroanatomical and molecular phenotypes relevant to ASD, including cell packing density and morphology in frontal cortex, amygdala, hippocampus and cerebellum, as well as profiling expression of a panel of putative ASD markers at the levels of mRNA and protein. Pten+/- mice provide a sensitized background in which PI3-kinase signaling is perturbed; this pathway is also implicated in the pathology of tuberous sclerosis with autism, thus making it an attractive target for modifier screening. Our results provide the basis for experiments that we are pursuing, examining modification of ASD-related phenotypes in these mice using double heterozygosity with other ASD candidate genes, as well as pharmacological and environmental manipulations.