Scn2a severe hypomorphic mutation decreases excitatory synaptic input and causes autism-associated behaviors

• Published in: JCI insight Vol. 6; no. 15
• Main Authors: Wang, Hong-Gang, Bavley, Charlotte C, Li, Anfei, Jones, Rebecca M, Hackett, Jonathan, Bayleyen, Yared, Lee, Francis S, Rajadhyaksha, Anjali M, Pitt, Geoffrey S
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 09.08.2021; American Society for Clinical investigation
• Subjects: Animal Communication; Animals; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - psychology; Behavior, Animal - physiology; Brain - pathology; Cells, Cultured; Correlation of Data; Disease Models, Animal; Gene Expression Regulation; Loss of Function Mutation; Mice; NAV1.2 Voltage-Gated Sodium Channel - genetics; Neurons - metabolism; Neuroscience; Mouse models; Neuroscience; Ion channels
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.150698

SCN2A, encoding the neuronal voltage-gated Na+ channel NaV1.2, is one of the most commonly affected loci linked to autism spectrum disorders (ASDs). Most ASD-associated mutations in SCN2A are loss-of-function mutations, but studies examining how such mutations affect neuronal function and whether Scn2a mutant mice display ASD endophenotypes have been inconsistent. We generated a protein truncation variant Scn2a mouse model (Scn2aΔ1898/+) by CRISPR that eliminates the NaV1.2 channel's distal intracellular C-terminal domain, and we analyzed the molecular and cellular consequences of this variant in a heterologous expression system, in neuronal culture, in brain slices, and in vivo. We also analyzed multiple behaviors in WT and Scn2aΔ1898/+ mice and correlated behaviors with clinical data obtained in human subjects with SCN2A variants. Expression of the NaV1.2 mutant in a heterologous expression system revealed decreased NaV1.2 channel function, and cultured pyramidal neurons isolated from Scn2aΔ1898/+ forebrain showed correspondingly reduced voltage-gated Na+ channel currents without compensation from other CNS voltage-gated Na+ channels. Na+ currents in inhibitory neurons were unaffected. Consistent with loss of voltage-gated Na+ channel currents, Scn2aΔ1898/+ pyramidal neurons displayed reduced excitability in forebrain neuronal culture and reduced excitatory synaptic input onto the pyramidal neurons in brain slices. Scn2aΔ1898/+ mice displayed several behavioral abnormalities, including abnormal social interactions that reflect behavior observed in humans with ASD and with harboring loss-of-function SCN2A variants. This model and its cellular electrophysiological characterizations provide a framework for tracing how a SCN2A loss-of-function variant leads to cellular defects that result in ASD-associated behaviors.