Female specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and Estrogen Receptor α

Abstract

SummaryAutism manifests differently in males and females and the brain mechanisms that mediate these sex-dependent differences are unknown. Here, we demonstrate that deletion of the ASD-risk gene,Pten,in neocortical pyramidal neurons (NSEPtenKO) results in robust hyperexcitability of local neocortical circuits in female, but not male, mice, observed as prolonged, spontaneous persistent activity states (UP states). Circuit hyperexcitability in females is mediated by enhanced signaling of metabotropic glutamate receptor 5 (mGluR5) and estrogen receptor α (ERα) to ERK andde novoprotein synthesis. In support of this idea,Ptendeleted cortical neurons have a female-specific increase in mGluR5 levels and mGluR5-driven protein synthesis rates, mGluR5-ERα complexes are elevated in female cortex and genetic reduction of ERα inPtenKO cortical neurons rescues circuit excitability, protein synthesis rates and enhanced neuron size selectively in females. Abnormal timing and hyperexcitability of neocortical circuits in femaleNSEPtenKO mice are associated with deficits in temporal processing of sensory stimuli and social behaviors as well as mGluR5-dependent seizures. Female-specific cortical hyperexcitability and mGluR5-dependent seizures are also observed in a human disease relevant mouse model, germlinePten+/-mice. Our results reveal molecular mechanisms by which sex and a high impact ASD-risk gene interact to affect brain function and behavior.