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Cell Type-Specific Roles of the Na-Activated K Current in KCNT1-Related Epilepsy

Award Number: R01NS130042
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Cell Type-Specific Roles of the Na-Activated K Current in KCNT1-Related Epilepsy - Variants in the KCNT1 gene, which encodes a Na+-activated K+ channel, cause several severe childhood epilepsy disorders that are largely refractory to treatment. Previously, pathogenic KCNT1 variants were shown to increase channel current when assayed in non-neuronal cells, leading to the fundamental question of how increasing a current that is usually associated with dampening neuronal excitability leads to disorders characterized by excessive, synchronous neuronal activity. We have created two mouse models with orthologous pathogenic human KCNT1 variants that have frequent seizures. In both models, cortical inhibitory neurons (cINs) show strong impairments in membrane excitability and action potential generation, whereas excitatory neurons (cENs) do not. These data suggest that KCNT1 gain-of-function (GOF) variants cause childhood epilepsy by impairing the function of cINs, and that KCNT1 channels play cell-type-specific roles in regulating neuronal excitability. This proposal will test these hypotheses by (1) determining how KCNT1 block and GOF affect membrane excitability of cIN subtypes, (2) using newly-developed KCNT1-selective inhibitors to measure the current and how it is altered by disease-causing variants in cIN subtypes, and (3) testing how impaired membrane excitability in subpopulations of cINs affects their activity in vivo, and how this relates to seizures or cortical hyperexcitability. Determining these vulnerable cell types, the underlying mechanisms, and the in vivo effects of their dysfunction will allow us to relate cellular deficits to epileptiform activity and seizures. The results will advance our understanding of the regulation of cIN excitability, the physiological roles of the KCNT1-mediated current, and the disease mechanisms of KCNT1 GOF in an in vivo model of epilepsy. This will narrow the knowledge gap between the biophysical effects of ion channel variants and the resulting dysfunction of networks, and has the potential to improve the targeting of precision therapies for severe childhood epilepsies.


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: 2026 ( Subtotal = $400,000 )
2026	2026	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	3/5/2026	NON-COMPETING CONTINUATION	$40,000
2026	2026	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/10/2025	NON-COMPETING CONTINUATION	$360,000
														Subtotal = $400,000

Issue Date FY: 2025 ( Subtotal = $400,000 )
2025	2025	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	8/5/2025	NON-COMPETING CONTINUATION	$40,000
2025	2025	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/14/2024	NON-COMPETING CONTINUATION	$360,000
2025	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	11/14/2024	NEW	$0
														Subtotal = $400,000

Issue Date FY: 2024 ( Subtotal = $388,000 )
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/16/2024	NON-COMPETING CONTINUATION	$28,000
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/13/2023	NON-COMPETING CONTINUATION	$360,000
														Subtotal = $388,000

Issue Date FY: 2023 ( Subtotal = $400,001 )
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	4/19/2023	NEW	-$389,999
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/30/2022	NEW	$390,000
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	4/20/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$400,000
														Subtotal = $400,001

Grand Total All Awards = $1,588,001

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Cell Type-Specific Roles of the Na-Activated K Current in KCNT1-Related Epilepsy

Award Number: R01NS130042

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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