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Neocortical and Hippocampal Circuit Dysfunction in the KCNT1 Model of Epilepsy

Award Number: R21NS133670
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: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Neocortical and Hippocampal Circuit Dysfunction in the KCNT1 Model of Epilepsy - Variants of the KCNT1 gene encoding the Na+ activated K+ channel results in intellectual disability and a range of developmental seizure disorders including epilepsy of infancy with migrating focal seizures and sleep-related hypermotor epilepsy. Prior in vitro electrophysiology in the KCNT1 knock-in variant mouse model showed that hypoexcitability of a non-fast spiking interneuron subtype in the frontal lobe was the likely cause of local seizure induction during Non-REM sleep, and contextual fear learning deficits. The extent to which the KCNT1 variant modifies circuit activity in limbic and frontal regions, and whether these changes result from interneuronopathy of somatostatin (SST+) or parvalbumin positive (PV+) cells, remain fundamental questions in this model. We therefore propose simultaneous high-density electrophysiological characterization and optogenetic testing of activity in dentate gyrus SST+ and PV+ interneuron subtypes. This approach provides unprecedented detail of the relationship between cell and circuit function in control and KCNT1 mice. Preliminary KCNT1 data show hypersynchronous hippocampal IEDs and significantly larger dentate spikes, suggesting alteration of the microcircuitry governing entorhinal-hippocampal pathways. We hypothesize that: A) Hypersynchronous oscillations the KCNT1 hippocampus result from failure of local SST+ interneuron inhibition and loss of regional circuit regulation; and B) Selective stimulation of SST+ interneurons, more so than PV+ interneurons, will rectify inhibitory function and attenuate inter-ictal epileptiform discharges (IEDs). These experiments could establish a necessary causal link between gene-induced interneuronopathy, cell function and circuit susceptibility to hyperexcitation and a novel approach for rescuing inhibitory regulation. We will also study the long-term effects of chronic cell-type selective stimulation on seizure and cognitive outcomes through long-term video and EEG monitoring and performance on the active avoidance behavioral task.


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 = $209,502 )
2026	2026	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/18/2025	NON-COMPETING CONTINUATION	$209,502
														Subtotal = $209,502

Issue Date FY: 2025 ( Subtotal = $207,387 )
2025	2025	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/26/2024	NEW	$207,387
														Subtotal = $207,387

Grand Total All Awards = $416,889

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Neocortical and Hippocampal Circuit Dysfunction in the KCNT1 Model of Epilepsy

Award Number: R21NS133670

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: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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