Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with a clear, but heterogeneous, genetic component. Germline mutations in the tumor suppressor PTEN are a well-established risk factor for ASD with macrocephaly, and conditional Pten mouse models have impaired social behavior and brain development. Some mutations observed in patients disrupt the normally balanced nuclear-cytoplasmic localization of the PTEN protein, and we developed the Pten(m3m4) model to study the effects of a cytoplasm-predominant Pten. In this model, germline mislocalization of Pten causes inappropriate social behavior with intact learning and memory, a profile reminiscent of high-functioning ASD. These animals also exhibit histological evidence of neuroinflammation and expansion of glial populations by six-weeks of age. We hypothesized that the neural transcriptome of this model would be altered in a manner that could inform human idiopathic ASD, a constitutional condition. Using total RNA-sequencing, we found progressive disruption of neural gene expression in Pten(m3m4) mice from two- to six-weeks of age, involving both immune and synaptic pathways. These alterations include downregulation of many highly co-expressed human-ASD-susceptibility genes. Comparison to a human cortical development coexpression network revealed that genes disrupted in Pten(m3m4) mice were enriched in the same areas as those of human ASD. While PTEN-related ASD is relatively uncommon, our observations suggest that the Pten(m3m4) model recapitulates multiple molecular features of human-ASD, and that Pten operates far upstream of common pathways within ASD pathogenesis.