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

> **NIH NIH R01** · PURDUE UNIVERSITY · 2024 · $68,934

## Abstract

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 i...

## Key facts

- **NIH application ID:** 11035317
- **Project number:** 3R01NS117585-04S1
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Yang Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $68,934
- **Award type:** 3
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11035317

## Citation

> US National Institutes of Health, RePORTER application 11035317, Neuronal and Behavioral Deficits Associated with Scn2a Deficiency in Autism Spectrum Disorder (3R01NS117585-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11035317. Licensed CC0.

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