PTEN and FMR1 are two susceptibility genes for autism spectrum disorder (ASD) that encode regulators of thePI3K-Akt-mTOR pathway. Phosphorylation of ribosomal protein S6 (p-S6) is a downstream readout of mTORactivity. Altered levels of p-S6 have been reported in the postmortem cerebral cortex of individuals with autismand in mouse models of autism risk factors. However, it is not known when during development and in whichcell types dysregulation of p-S6 signaling occurs and whether this contributes to the symptoms of ASD. Ourgoal is to identify common cell types and time windows in which p-S6 is dysregulated across two mousemodels of autism risk factors, Pten and Fmr1, and to study the relationship between p-S6 dysregulation andsocial behavioral deficits. The novel hypothesis we develop here is that cell types that are normally enrichedfor p-S6 in the developing brain are selectively vulnerable to overgrowth caused by Pten or Fmr1 mutations.We propose to carry out this work by using an innovative combination of mapping the activity of a signalingpathway (PI3K-Akt-mTOR/p-S6) key to cellular growth and ASD pathogenesis in the developing brain atunprecedented spatiotemporal resolution, neuroanatomical tracing and behavioral phenotyping to determinewhen and where dysregulation of p-S6 might contribute to the pathophysiology of ASD risk factors. In additionto understanding molecular and cellular mechanism of social behavioral deficits, this will also test thetherapeutic potential of targeting mTOR/p-S6 signaling during a critical developmental time window as astrategy for treating ASD.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
