Friday, October 3, 2025 10/3/2025

Inhibitory neuron dysfunction in intellectual disability and epilepsy

Award Number: F30HD114410
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/15/2024
PERIOD OF PERFORMANCE END DATE: 05/14/2027

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Inhibitory neuron dysfunction in intellectual disability and epilepsy - 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 changes that result in the observed phenotypes. This contribution will be significant because the pathophysiologic alterations identified from this study will guide molecular investigations of therapeutic targets in addition to contributing to discoveries of common mechanisms of intellectual disability and epilepsy in NDDs.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $51,660 )
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	2	3/10/2025	NON-COMPETING CONTINUATION	$51,096
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	001	2	6/4/2025	NON-COMPETING CONTINUATION	$564
														Subtotal = $51,660

Issue Date FY: 2024 ( Subtotal = $48,541 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	001	1	3/14/2024	NEW	$0
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Child Health and Human Development Extramural Research	000	1	3/14/2024	NEW	$48,541
														Subtotal = $48,541

Grand Total All Awards = $100,201

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Inhibitory neuron dysfunction in intellectual disability and epilepsy

Award Number: F30HD114410

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/15/2024

PERIOD OF PERFORMANCE END DATE: 05/14/2027

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