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Neuronal hyperexcitability and seizures in a Scn2a deficient mouse model

Award Number: R01NS123154
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: 07/15/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Neuronal hyperexcitability and seizures in a Scn2a deficient mouse model - Project Summary/Abstract Genetic studies in humans revealed that gain-of-function variants of SCN2A are associated with epilepsy, whereas loss-of-function variants of SCN2A are associated with autism spectrum disorder (ASD). However, about a third of ASD children carrying SCN2A loss-of-function or nonsense variants (collectively referred to as SCN2A deficiency) develop intractable seizures, major comorbidity associated with ASD. How SCN2A deficiency contributes to seizure is largely unknown. To address this problem, we generated a Scn2a-deficient mouse model by gene-trap knockout (gtKO) strategy. Homozygous gene-trap knockout mice have only a quarter of the Scn2a expression level of WT mice, which model severe Scn2a deficiency. Our preliminary patch-clamp recordings reveal that neurons with severe Scn2a deficiency displayed neuronal hyperexcitability. This finding is unexpected, but could open the door for the understanding of the puzzling seizure comorbidity in SCN2A deficiency-related ASD. However, critical gaps exist regarding the possible mechanisms underlying Scn2a deficiency-related neuronal hyperexcitability, its consequences on neural network and seizures susceptibility, as well as the reversibility of seizures-related phenotypes. Filling these gaps would greatly enhance understanding of the mechanisms underlying seizure comorbidity in ASD; and shed new light on the development of effective therapeutic interventions. To this end, here we propose to test an overarching hypothesis that a substantial reduction of Scn2a expression results in increased neuronal excitability related to K channel downregulation, hypersynchronization of in vivo firing, and elevated seizure susceptibility that can be reversed by targeted genetic interventions. We will test our hypothesis at the cellular, circuit, and in vivo levels. In Aim 1, we will assess ex vivo neuronal excitability of Scn2a-deficient mice. In Aim 2, we will determine in vivo neuronal firings and seizure susceptibility of the Scn2a-deficient mice. In Aim 3, we will test targeted genetic interventions. Our study is significant in the following ways: i) SCN2A deficiency is among the leading monogenetic forms of ASD and seizure comorbidity occurs in about 30% of affected ASD patients; ii) The finding that severe SCN2A deficiency resulting in hyperexcitability is potentially paradigm-shifting, and the study of which could reveal key insights regarding seizure comorbidity associated with ASD; and iii) Targeted genetic interventions to be evaluated have clear translational relevance. Our study has the following innovations: i) the use of novel Scn2a deficient mice that reveal unexpected finding of neuronal hyperexcitability; ii) innovative ways to achieve genetic rescue; and iii) the use of cutting-edge technologies including high-density Neuropixels recordings. The applicant is an early stage investigator (ESI), whose team has extensive expertise in sodium channel physiology, genetics, electrophysiology, and pharmacology. The team is well suited to carry out the proposed work to its full completion within the project timeframe, and generate impactful outcomes to advance the field.


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 = $0 )
2026	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/17/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $387,500 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/5/2025	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2024 ( Subtotal = $375,875 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/15/2024	NON-COMPETING CONTINUATION	$375,875
														Subtotal = $375,875

Issue Date FY: 2023 ( Subtotal = $387,500 )
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/13/2023	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2022 ( Subtotal = $387,500 )
2022	2022	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/12/2022	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2021 ( Subtotal = $387,500 )
2021	2021	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/5/2021	NEW	$387,500
														Subtotal = $387,500

Grand Total All Awards = $1,925,875

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Neuronal hyperexcitability and seizures in a Scn2a deficient mouse model

Award Number: R01NS123154

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: 07/15/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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