# Inhibitory neuron dysfunction in intellectual disability and epilepsy

> **NIH NIH F30** · BAYLOR COLLEGE OF MEDICINE · 2024 · $48,541

## Abstract

PROJECT SUMMARY
CASK encodes the synaptic protein calcium/calmodulin-dependent serine protein kinase and is one of the five
most common X-linked genes with de novo variants in developmental disorders. Loss-of-function variants in
CASK result in a heterogeneous syndrome collectively known as CASK-related disorders (CRDs) with hallmark
symptoms including intellectual disability (ID) and epilepsy. These patients, like many other children with rare
neurodevelopmental disorders (NDDs), are clinically underserved without pharmacotherapies for ID and with
increased resistance to anti-seizure medications. There is a critical need to understand the neuronal
mechanisms of CRDs to identify targets for therapeutics to address this gap. While mouse models of CRDs have
epilepsy, they have not yet been investigated for cognitive deficits, despite ID being the most penetrant symptom
in patients. Conditional Cask KO in inhibitory neurons has recapitulated epileptic phenotypes with preliminary
data suggesting altered synaptic function. Thus, the central hypothesis is that Cask dysfunction in inhibitory
neurons causes both cognitive deficits and epilepsy due to impaired synaptic transmission. This will be studied
through genetic manipulations in combination with various techniques. Aim 1 will test the mouse model for
cognitive deficits and determine the contribution of inhibitory neuron specific Cask KO to the phenotype; Aim 2
will investigate changes in inhibitory neuron pre-synaptic output via paired whole-cell patch clamp; and Aim 3
will determine inhibitory neuron post-synaptic input changes via ex vivo whole-cell patch clamp and how these
changes translate into in vivo neuronal activity via two-photon Ca2+ imaging. The overall goal of this project uses
mouse models to determine how the loss of Cask in inhibitory neurons alters synaptic function to result in disease
pathogenesis and is designed to prepare the applicant for a career as a pediatric neurologist specializing in
treating patients with and studying NDDs. This project furthers the applicant’s long-term goal of understanding
cortical interneuron development and homeostasis and how perturbations result in NDDs, with the end goal of
developing novel therapeutics. The Xue lab has a strong track-record of successful MSTP trainees and conducts
impactful research using mouse models of human NDDs to discover neuronal mechanisms that contribute to
disease. Furthermore, the collaborative training environment of both Baylor College of Medicine and the Jan and
Dan Duncan Neurologic Research Institute provide state-of-the-art technology cores, experts in the field of
NDDs, and a central location in the Texas Medical Center that will facilitate the success of the project and training
of the applicant. The proposed research is expected to elucidate how inhibitory neuron dysfunction contributes
to cognitive deficits and epilepsy in mouse models of CASK-related disorders and the concomitant synaptic input
and output c...

## Key facts

- **NIH application ID:** 10902769
- **Project number:** 1F30HD114410-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Kevin Jiang
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,541
- **Award type:** 1
- **Project period:** 2024-03-15 → 2027-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10902769

## Citation

> US National Institutes of Health, RePORTER application 10902769, Inhibitory neuron dysfunction in intellectual disability and epilepsy (1F30HD114410-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10902769. Licensed CC0.

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