Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders that share deficits in sociability, communication, and restrictive and repetitive interests. ASD is likely polygenic in origin in most cases, but we presently lack an understanding of the relationships between ASD susceptibility genes and the neurobiological and behavioral phenotypes of ASD. Two genes that have been implicated as conferring susceptibility to ASD are PTEN and Serotonin transporter (SLC6A4). The PI3K and serotonin pathways, in which these genes respectively act, are both potential biomarkers for ASD diagnosis and treatment. Biochemical evidence exists for an interaction between these pathways; however, the relevance of this for the pathogenesis of ASD is unclear. We find that Pten haploinsufficient (Pten ؉/؊ ) mice are macrocephalic, and this phenotype is exacerbated in Pten ؉/؊ ; Slc6a4 ؉/؊ mice. Furthermore, female Pten ؉/؊ mice are impaired in social approach behavior, a phenotype that is exacerbated in female Pten ؉/؊ ; Slc6a4 ؉/؊ mice. While increased brain size correlates with decreased sociability across these genotypes in females, within each genotype increased brain size correlates with increased sociability, suggesting that epigenetic influences interact with genetic factors in influencing the phenotype. These findings provide insight into an interaction between two ASD candidate genes during brain development and point toward the use of compound mutant mice to validate biomarkers for ASD against biological and behavioral phenotypes.autism ͉ brain development ͉ brain growth A utism spectrum disorder (ASD) is highly heritable, with a 2-3% recurrence rate in siblings and a 60-90% concordance rate in monozygotic twins. However, known genetic causes-for example, single gene disorders such as fragile-X or tuberous sclerosis-account for Ϸ10% of ASD cases. Thus, the majority of cases of ASD are of unknown cause at present. Current estimates are that ASD susceptibility is conferred by numerous genes interacting with one another and with environmental factors.Two genes that give insight into idiopathic autism are PTEN and SLC6A4. PTEN acts as a negative regulator of the PI3-kinase (PI3K) pathway (1). Heterozygous PTEN mutations have been identified in a subset of individuals with autism and macrocephaly, thus rendering affected individuals PTEN haploinsufficient (2-5). The clinical-phenotypic presentation of cognitive impairment in PTEN haploinsufficient individuals is varied. Thus, it has been suggested that individuals with ASD who carry PTEN mutations may represent a sensitized group in which to screen for second-site genetic modifiers of the ASD clinical phenotype (4). SLC6A4 encodes membrane-bound transporter of serotonin that influences extracellular levels of this neurotransmitter. SLC6A4 has been implicated as both an ASD candidate susceptibility gene and a second-site genetic modifier in ASD (6, 7). Brain overgrowth (8) and severe social behavioral impairments (9) have been reported in individuals wit...
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