# Sex-specific mechanisms of cortical circuit dysfunction in a mouse ASD model

> **NIH NIH R37** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $2,096,266

## Abstract

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...

## Key facts

- **NIH application ID:** 10052919
- **Project number:** 1R37NS114516-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** KIMBERLY M. HUBER
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,096,266
- **Award type:** 1
- **Project period:** 2020-08-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052919

## Citation

> US National Institutes of Health, RePORTER application 10052919, Sex-specific mechanisms of cortical circuit dysfunction in a mouse ASD model (1R37NS114516-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10052919. Licensed CC0.

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