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

> **NIH NIH R37** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $511,174

## Abstract

Increasing evidence indicates that Autism Spectrum Disorder (ASD) is manifests differently in males and females
behaviorally and affects brain function and connectivity differently between sexes. There has been little known
of how ASD genes affect the female brain on a cellular and microcircuit level. During the previous grant period
we discovered that deletion of the ASD-risk gene, Pten (Phosphatase and tensin homolog deleted on
chromosome 10), in neocortical pyramidal neurons (NSEPten KO) resulted in robust hyperexcitability of local
neocortical circuits in female, but not male, mice, observed as prolonged, spontaneous persistent activity states
(UP states). We also demonstrated that circuit hyperexcitability in NSEPten KO mice is mediated by enhanced
signaling of metabotropic glutamate receptor 5 (mGluR5) and estrogen receptor α (ERα) to ERK and de novo
protein synthesis selectively in Pten deleted female neurons. Pten deleted Layer 5 cortical neurons have a
female-specific increase in mGluR5 levels and mGluR5-driven protein synthesis. In addition, mGluR5-ERα
complexes are elevated in female cortex and genetic reduction of ERα in Pten KO cortical neurons rescues
circuit excitability, protein synthesis and enhanced neuron size selectively in females. Abnormal timing and
hyperexcitability of neocortical circuits in female NSEPten KO 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, germline Pten+/- mice. Our results demonstrate sex-specific dysfunction of developing cortical circuits
with loss of function of a high-confidence ASD-risk gene. Importantly, we demonstrate a distinct, female-specific
dysfunction of mGluR5- ERα signaling pathways that drive excitability. For the Phase 2 extension of this work,
we propose to determine the female-specific, Pten-regulated cellular and molecular alterations in cortical
neurons that give rise to hyperexcitability of circuits. In Aim 1, we will determine the sex-specific, mGluR5 and
ERα -regulated neuronal and synaptic properties in L5 PTEN KO neurons. In Aim 2 we will determine the sex-
specific, PTEN-regulated ribosome- associated transcripts in L5 cortical neurons and their regulation by mGluR5
and ERα. Our results reveal sex-specific and estrus cycle-dependent deficits in sensory-processing in Pten loss
of function models. In Aim 3 we will determine if a reduction in mGluR5 or ERα function corrects these sensory
processing deficits and in Aim 4, we will examine the role of estrogen and estrus cycle in dysfunction of
developing and mature cortical circuits and in vivo resting and sensory-driven EEG phenotypes in Pten loss of
function models. Results of these aims are expected to provide knowledge of the sex-specific mechanisms by
which ASD-risk genes regulate the development and function of ...

## Key facts

- **NIH application ID:** 11058767
- **Project number:** 4R37NS114516-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** KIMBERLY M. HUBER
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $511,174
- **Award type:** 4N
- **Project period:** 2024-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11058767

## Citation

> US National Institutes of Health, RePORTER application 11058767, Sex-specific mechanisms of cortical circuit dysfunction in a mouse ASD model (4R37NS114516-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11058767. Licensed CC0.

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