Deciphering SCN2A: A comprehensive review of rodent models of Scn2a dysfunction

Abstract

SCN2A encodes for the alpha subunit of the voltage-gated sodium channel Na_V1.2, which is involved in action potential initiation and backpropagation in excitatory neurons. Currently, it is one of the highest monogenetic risk factors for both epilepsy and autism spectrum disorder. However, SCN2A-related disorders manifest in a broad clinical neuropsychiatric spectrum, including distinct neurological and psychiatric disorders. This clinical heterogeneity presents challenges for mechanistic understanding and treatment development. SCN2A mutations are generally classified as either gain-of-function (GOF) or loss-of-function (LOF); however, many mutations do not perfectly align to this binary framework. SCN2A dysfunction alters neuronal excitability, channel kinetics, and synaptic transmission in various ways, resulting in multiple electrophysiological effects and both seizure and behavioral phenotypes that are influenced by developmental stage, brain region, genetic background, and sex. Although early lethality in GOF models limits behavioral characterization, LOF models broadly show patterns of learning impairments, altered sociability, and disrupted sensory processing. Still, behavioral and seizure phenotypes are often inconsistent even across models with similar or identical variants, suggesting that genetic modifiers, such as potassium channels, play a role in shaping disease outcomes. Overall, these findings suggest that SCN2A-related disorders involve complex gene-gene and gene-environment interactions, rather than only channel biophysics. Current therapeutic strategies include Clustered Regularly Interspaced Short Palindromic Repeat-mediated transcriptional activation (CRISPRa), antisense oligonucleotides, and deep brain stimulation; however, they are limited due to variant specificity or age of intervention. This review highlights areas of convergence and conflict across models, emphasizing knowledge gaps, such as the limited availability of data on early development. Ultimately, it emphasizes the importance of investigating models across different developmental stages, using diverse genetic background strains, among other approaches, to encourage therapeutic innovation and enhance care for patients. We hope this work contributes to the emerging unifying framework that looks beyond the GOF and LOF binary in SCN2A-related disorders.

Keywords: Nav1.2; autism; epilepsy; therapeutics.

FIGURE 1

Na_v1.2 dysfunction impacts glutamatergic cortical neuron activity differently depending on developmental stage. (AP= Acttion Potential, AIS = Axon intial segment)  Created in BioRender. Williams lab, A. (2025) https://BioRender.com/aq9xdz6.

FIGURE 2

Summarized findings of olfaction‐related behaviors in Scn2a mouse models. Behaviors are separated by age at time of assessment. Blue lines indicate an increase in the behaviors observed in that assay, red lines indicate a decrease in the behaviors observed in that assay, and black small‐dotted lines indicate no change. Large‐dashed lines are utilized to indicate trends and colored red or blue to indicate the direction of the trend. Created in BioRender. Williams lab, A. (2025) https://BioRender.com/pglh067.

FIGURE 3

Table of additional modifiers identified in Scn2a ^Q54 mice. Created in BioRender. Williams lab, A. (2025) https://BioRender.com/l21j948.

FIGURE 4

(A) Summary of results from learning and memory related assays in Scn2a mouse models. (B) Summary of results from motor behavior related assays in Scn2a mouse models. (C) Summary of results from anxiety‐like behavioral assays in Scn2a mouse models. (D) Summary of results from assays related to repetitive behaviors in Scn2a mouse models. Behaviors in A, B, C and D are broken down by age at time of assessment. Blue lines indicate an increase in the behaviors observed in that assay, red lines indicate a decrease in the behaviors observed in that assay, and black small‐dotted lines indicate no change. Large‐dashed lines are utilized to indicate trends and colored red or blue to indicate the direction of the trend. Created in BioRender. Williams lab, A. (2025) https://BioRender.com/sa0eb87.

FIGURE 5

Summary of results related to sociability and social novelty in Scn2a mouse models. Behaviors are separated by age at time of assessment. Blue lines indicate an increase in the behaviors observed in that assay, red lines indicate a decrease in the behaviors observed in that assay, and black small‐dotted lines indicate no change. Large‐dashed lines are utilized to indicate trends and colored red or blue to indicate the direction of the trend. Created in BioRender. Williams lab, A. (2025) https://BioRender.com/rfd40nf.