# Examining the role of specific NMDA receptor subunits in cortical circuit dysfunction in Fragile X Syndrome

> **NIH NIH F31** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $39,712

## Abstract

PROJECT SUMMARY
Sensory hypersensitivity is a common symptom in autism and Fragile X Syndrome (FXS) and is thought to be a
result of cortical circuit dysregulation. EEG studies in humans with FXS and the FXS mouse model, the Fmr1
KO, reveal cortical circuit hyperexcitability and synchrony deficits such as enhanced resting state power in the
gamma band and reduced sensory-driven synchrony. In acute slices, this hyperexcitability can be observed as
prolonged persistent activity states, called UP states, and increased gamma band power during UP states. I
hypothesize that circuit mechanisms that mediate hyperexcitability and prolonged UP states in the neocortex
may contribute to EEG phenotypes in FXS. Using positive and negative allosteric modulators (PAMs/NAMs)
specific for GluN2C/D subunits of NMDA receptors, I have revealed an upregulation of GluN2C/D function in the
Fmr1 KO cortex that contributes to circuit hyperexcitability. Specifically, GluN2C/D PAMs increase UP state
duration and gamma power during the UP states, while NAMs rescue UP state duration. Remarkably, these
interventions only affected the Fmr1 KO, not their wildtype (WT) littermates suggesting that GluN2C/D function
is upregulated in the Fmr1 KO and leads to cortical circuit dysfunction. Typically, GluN2C/D subunits are
expressed in cortical inhibitory neurons and astrocytes. Since my results are not consistent with effects on
inhibitory neurons, GluN2C/D subunits may be misexpressed in excitatory neurons or upregulated in astrocytes
in the Fmr1 KO. I hypothesize that GluN2C/D expression and/or function is increased in excitatory
neurons and/or astrocytes in Fmr1 KO mice and this contributes to hyperexcitability and altered
synchrony of cortical circuits. The goal of the proposed project is to test this hypothesis and determine
expressional and functional changes in Glun2C/D that may contribute to cortical hyperexcitability and synchrony
following three Specific Aims. Aim 1. To determine change in cortical protein and RNA expression levels as well
as cell specific expression of GluN2C/D subunits in Fmr1 KO cortex. Aim 2. To determine cell specific functional
contribution of GluN2C/D subunits to NMDA-mediated currents in WT and Fmr1 KO cortex. Aim 3. To determine
the contribution of GluN2C/D NMDARs to in vivo sensory driven circuit excitability and altered synchrony using
multi-electrode array EEG and measurement of audiogenic seizures in the Fmr1 KO mouse in collaboration with
Dr. Devin Binder at UC Riverside. These experiments will not only provide insights into the molecular and cellular
basis of GluN2C/D contribution to cortical circuit dysfunction, but also examine GluN2C/D subunits as a potential
target for therapeutic development using translational biomarkers.

## Key facts

- **NIH application ID:** 10926838
- **Project number:** 5F31HD113236-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Aleya Michelle Shedd
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $39,712
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10926838

## Citation

> US National Institutes of Health, RePORTER application 10926838, Examining the role of specific NMDA receptor subunits in cortical circuit dysfunction in Fragile X Syndrome (5F31HD113236-02). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10926838. Licensed CC0.

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