Although ASD is more diagnosed in males, the behavioral manifestations of ASD, as well as the neuroanatomical changes and brain dysfunction associated with ASD, differ between males and females. There is little known of how ASD genes impact the female brain. Estrogen, acting through membrane bound estrogen receptor α (ERα), interacts with and activates Gq-coupled Group 1 mGluRs, mGluR1 and mGluR5, selectively in female neurons in diverse brain regions to regulate signaling, neurophysiology, and behavior. Altered functioning of mGluRs, primarily mGluR5, is strongly implicated in the pathophysiology of ASD mouse models, most notably Fragile X Syndrome, but many others, and mGluR5 antagonists are in clinical trials of FXS children. We were the first to discover hyperactivity of mGluR5 function in the FXS mouse model, Fmr1 KO, and show this results from an abnormal mGluR5 complex; mGluR5 is dissociated from its postsynaptic scaffolding protein, Homer, which, in turn, leads to constitutive mGluR5 activity, abnormal signaling to downstream effectors and disease relevant phenotypes, such as circuit hyperexcitability. Despite the evidence for mGluR5 in ASD pathophysiology, the known sex-dependent regulation of mGluR1/5 by estrogen, little is known of how ASD-linked genes interact with estrogen to affect mGluR1/5 function and the consequences on ASD-relevant neurophysiology and behavior. We have discovered a sex-specific, mGluR5 -dependent dysfunction of sensory neocortical circuits in a mouse model of ASD that results from deletion of Pten (Phosphatase and tensin homolog deleted on chromosome 10), a suppressor of the PI3K/mTORC1 pathway. Specifically, we observe hyperexcitable neocortical circuit oscillations, termed UP states, in females of two distinct PTEN deletion models; an embryonic, knockout of Pten in hippocampus and layer 5 neocortical neurons, and a germline Pten heterozygous mouse (Pten-het), which is a genetically valid model for Pten-related ASD in humans. Hyperexcitable UP states in female Pten models are corrected by acute antagonism of mGluR5 or ERα, indicative of hyperactive mGluR5- ERα signaling. A candidate molecular substrate for enhanced mGluR5-ERα activity is the observed increase in mGluR5-ERα, and decreased mGluR5-Homer, complexes in female Pten-het cortex. We hypothesize that an imbalance in mGluR5 interactions with ERa and Homer in Pten deleted female neurons results in enhanced mGluR5-signaling in response to estrogen, acting on ERα, as well as constitutively active mGluR5 which leads to hyperexcitable cortical oscillations and ASD-relevant behaviors. We propose the following aims to test this hypothesis: Aim 1: Determine the sex-dependent interactions of Pten and ERα in cortical circuit dysfunction and mGluR5 complex regulation. Aim 2: Examine the sex-specific effects of mGluR5 and ERα on intrinsic and synaptic properties of Pten-deleted layer 5 neurons. Aim 3: Determine the sex-specific, mGluR5- and ERα-dependent in vivo cort...