# Molecular and circuit defects underlying different SCN2A mutations and ASDs

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $643,410

## Abstract

ABSTRACT
 The recent wave of whole exome sequencing studies places SCN2A, which encodes the neuronal voltage-
gated Na+ channel pore-forming α subunit NaV1.2, near top of the list of genetic loci linked to autism spectrum
disorders (ASDs). On the one hand, that NaV1.2 is an essential Na+ channel responsible for initiating action
potentials within excitatory neurons in the developing brain provides a rationale for the prominence of SCN2A.
On the other, most SCN2A mutations associated with ASDs are loss-of-function and predicted to decrease
neuronal excitability, an outcome that would lower the neocortical excitation/inhibition (E/I) balance and thus
contrast with the generally accepted model that behavior defects in ASDs, such as social dysfunction, result
from an increased E/I balance. This conundrum persists because of the absence of Scn2a mouse models that
reveal ASD-associated endophenotypes, thus limiting our ability to dissect the cellular electrophysiological
defects associated with Scn2a loss-of-function mutations and the consequent circuit level dysfunctions that
lead to ASD-associated behaviors. Building on x-ray crystal structures of key regulatory components of NaV1.2
that we solved and analyzed during the previous funding period, we obtained specific insights into how ASD-
associated mutations in NaV1.2 perturb channel function and alter E/I balance. Further, we generated two
novel Scn2a mouse models by CRISPR/Cas9 to test the specific contribution of Scn2a mutations in vivo. Initial
analyses of these models reveal abnormal Na+ channel function, decreased cortical neuron excitability, and
dysfunctional behaviors consistent with ASDs, while simultaneously demonstrating informative differences
between the two models. These models provide a unique set of tools that will allow us to trace abnormal
channel function through altered neuronal electrical activity to the consequent circuit-level dysfunction and the
resulting ASD endophenotypes.
 We propose to exploit these novel Scn2a mutant models for the following Aims: 1) We will obtain detailed
information about their neuronal electrophysiological characteristics and synaptic properties, thereby defining
how Scn2a mutations perturb neuronal function. 2) We will employ fiber photometry and chemogenetic tools
(DREADDs) to test whether the Scn2a mutations decrease excitatory drive to the basolateral amygdala and
thereby produce the social dysfunction and impaired danger detection observed in our Scn2a mouse models.
3) We will exploit our initial electrophysiological findings to test a potential therapeutic strategy in which we aim
to counteract the reduced Na+ current associated with ASD-associated SCN2A loss-of-function mutations. Our
overall goals are to define the range of cellular dysfunction that results from Scn2a mutations and trace those
abnormalities through the circuit level to behavioral manifestations.

## Key facts

- **NIH application ID:** 9948006
- **Project number:** 5R01MH118934-07
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Geoffrey S Pitt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $643,410
- **Award type:** 5
- **Project period:** 2019-06-07 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948006

## Citation

> US National Institutes of Health, RePORTER application 9948006, Molecular and circuit defects underlying different SCN2A mutations and ASDs (5R01MH118934-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9948006. Licensed CC0.

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