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Neuronal and Behavioral Deficits Associated with Scn2a Deficiency in Autism Spectrum Disorder

Award Number: R01NS117585
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Neuronal and Behavioral Deficits Associated with Scn2a Deficiency in Autism Spectrum Disorder - Project Summary/Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with impaired social communications and behavioral abnormalities, which affects ~1 in 54 children in the United States (CDC.gov). SCN2A, encoding neuronal voltage-gated sodium channel Nav1.2, has been identified as one of the leading genes associated with ASD. We have characterized a novel Scn2a-deficient mouse model that is generated via targeted gene-trap knockout (gtKO) strategy and possesses a built-in genetic rescue element. Our preliminary data revealed profound behavioral abnormalities in homozygous Scn2agtKO/gtKO mice including anxiety-like behaviors, impaired nesting and social deficits. We also identified elevated excitation-inhibition (E/I) balance in pyramidal neurons of mPFC, which has been implicated in ASD and social deficits. However, a critical gap exists regarding how in vivo neuronal firings in mPFC are affected by elevated E/I balance and to what extent the manipulation of E/I balance will alter the behavioral outcomes in Scn2agtKO/gtKO mice. To address this gap, we propose to test an overarching hypothesis that Scn2a deficiency increases E/I balance, impairs neuronal responses in mPFC, and results in social deficits that can be rescued with targeted genetic and pharmacological interventions. In Aim 1, we will assess the synaptic properties and in vivo firing of neurons in mPFC using brain- slice patch-clamp recording and Neuropixels in vivo recording. Our findings are expected to provide cellular-level and local network level neuropathological mechanisms of Scn2a deficiency. In Aim 2, we will determine neuronal firings and behavioral outcomes in response to manipulating E/I balance in mPFC microcircuit using optogenetics and chemogenetics. Our findings will bolster the significance of E/I balance modulation for correction of behavioral deficits. In Aim 3, we will evaluate the efficacy of timed genetic and pharmacological rescue to determine optimal windows for intervention. Our study is significant in the following ways: i) SCN2A deficiency to be studied is among the leading monogenetic forms of ASD; ii) Excitation and inhibition (E/I) balance of mPFC microcircuit to be thoroughly dissected is closely associated with social deficits; and iii) Genetic rescue and pharmacological intervention to be tested are of clear clinical relevance, and will provide translational basis to inform therapeutic development for the treatment of Scn2a-deficiency related disorders. Our study has the following innovations: i) use of novel Scn2agtKO/gtKO mice that display profound cellular and behavioral deficits; ii) innovative ways to achieve genetic and pharmacological rescue; and iii) use of cutting-edge technologies including high density Neuropixels in vivo recordings. The applicant is an early stage investigator (ESI), whose team has extensive expertise in sodium channel electrophysiology, animal behaviors, genetics 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: 2025 ( Subtotal = $343,345 )
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	3/26/2025	NON-COMPETING CONTINUATION	$343,345
														Subtotal = $343,345

Issue Date FY: 2024 ( Subtotal = $438,983 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	4/24/2024	NON-COMPETING CONTINUATION	$26,704
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/15/2024	SUPPLEMENT FOR EXPANSION	$68,934
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	3/25/2024	NON-COMPETING CONTINUATION	$343,345
														Subtotal = $438,983

Issue Date FY: 2023 ( Subtotal = $381,494 )
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	3/17/2023	NON-COMPETING CONTINUATION	$381,494
														Subtotal = $381,494

Issue Date FY: 2022 ( Subtotal = $381,494 )
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	3/31/2022	NON-COMPETING CONTINUATION	$381,494
														Subtotal = $381,494

Issue Date FY: 2021 ( Subtotal = $381,494 )
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	3/30/2021	NEW	$381,494
														Subtotal = $381,494

Grand Total All Awards = $1,926,810

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Neuronal and Behavioral Deficits Associated with Scn2a Deficiency in Autism Spectrum Disorder

Award Number: R01NS117585

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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