Haploinsufficiency for Pten and Serotonin transporter cooperatively influences brain size and social behavior

Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1989-94. doi: 10.1073/pnas.0804428106.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder / genetics*
  • Brain*
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Haplotypes / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Organ Size
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / physiology*
  • Phenotype
  • Serotonin Plasma Membrane Transport Proteins / genetics
  • Serotonin Plasma Membrane Transport Proteins / physiology*
  • Sex Factors
  • Social Behavior*


  • Serotonin Plasma Membrane Transport Proteins
  • PTEN Phosphohydrolase
  • Pten protein, mouse