# Cellular and molecular mechanisms of auditory processing deficits in a mouse model of Fragile X Syndrome

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2021 · $18,944

## Abstract

PROJECT SUMMARY/ABSTRACT
Fragile X Syndrome (FXS) is a common monogenic form of autism spectrum disorder (ASD). Symptoms of
FXS include anxiety, intellectual disability, repetitive behaviors, social communication deficits, and abnormal
sensory processing. Our previous studies have shown that elevated levels of Matrix Metalloproteinase-9
(MMP-9) contribute to the hyper-responsiveness of auditory cortex in Fmr1 KO mice by affecting perineuronal
net (PNN) formation around parvalbumin (PV)-expressing inhibitory interneurons. Abnormal development of
PV neurons most likely contribute to abnormal electroencephalography (EEG)-based phenotypes of auditory
hypersensitivity in the Fmr1 KO mice that are remarkably similar to those seen in humans with FXS. We
recently showed that embryonic deletion of Fmr1 in cortical excitatory neurons is sufficient to elicit cellular,
electrophysiological, and behavioral phenotypes in Fmr1 KO mice. However, how the expression of Fmr1 in
different cell types shapes normal cortical responses during circuit development is not known. Altered auditory
responses in humans with FXS and Fmr1 KO animals suggest that abnormal development of the auditory
circuits may underlie the deficits. PV/PNN deficits are first observed after the hearing onset at around postnatal
day (P) 10 and hypersensitive neuronal circuits develop during third postnatal week (P14-P21 period). This
period coincides with the critical period plasticity (CPP) window in the rodent auditory cortex, a postnatal
window of structural and functional circuit development driven by sensory input. Synaptic and intrinsic
properties of auditory cortex neurons also mature during this time window. Since the development of acoustic
representations in primary auditory cortex is profoundly influenced by early experience, this project aims to:
1) determine whether deletion or rescue of Fmr1 in cortical excitatory neurons during the early postnatal period
is sufficient to trigger or prevent the development of abnormal phenotypes in the auditory cortex of a mouse
model of FXS, and 2) determine whether astrocyte-specific deletion of Fmr1 in developing or adult brain is
sufficient to trigger abnormal phenotypes in the auditory cortex of a mouse model of FXS. This will be achieved
through Cre-mediated deletion of Floxed Fmr1 gene in cortical excitatory neurons during P14-P21 period using
CaMK2a (CreCaMk2a) promoter, or astrocytes using GFAP (ERT2-CreGFAP) promoter. My proposed research will
use a multidisciplinary approach including electrophysiological (EEG), cellular, molecular, and behavioral
methods to delineate how cell-specific deletion of Fmr1 during early postnatal period contributes to auditory
hypersensitivity in FXS. Since these studies use clinically related techniques (i.e. EEG/MEA) to validate
biomarkers relevant for neurodevelopmental disorders, this analysis will allow for a more direct comparison of
animal-based research findings to human clinical studies.

## Key facts

- **NIH application ID:** 10134106
- **Project number:** 5F31NS117178-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Maham Rais
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $18,944
- **Award type:** 5
- **Project period:** 2020-04-01 → 2021-06-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134106

## Citation

> US National Institutes of Health, RePORTER application 10134106, Cellular and molecular mechanisms of auditory processing deficits in a mouse model of Fragile X Syndrome (5F31NS117178-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134106. Licensed CC0.

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