Title | Scn2a severe hypomorphic mutation decreases excitatory synaptic input and causes autism-associated behaviors. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Wang, H-G, Bavley, CC, Li, A, Jones, RM, Hackett, J, Bayleyen, Y, Lee, FS, Rajadhyaksha, AM, Pitt, GS |
Journal | JCI Insight |
Volume | 6 |
Issue | 15 |
Date Published | 2021 08 09 |
ISSN | 2379-3708 |
Keywords | Animal Communication, Animals, Autism Spectrum Disorder, Behavior, Animal, Brain, Cells, Cultured, Correlation of Data, Disease Models, Animal, Gene Expression Regulation, Loss of Function Mutation, Mice, NAV1.2 Voltage-Gated Sodium Channel, Neurons |
Abstract | 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. |
DOI | 10.1172/jci.insight.150698 |
Alternate Journal | JCI Insight |
PubMed ID | 34156984 |
PubMed Central ID | PMC8410058 |
Grant List | R01 HL122967 / HL / NHLBI NIH HHS / United States T32 DA039080 / DA / NIDA NIH HHS / United States R01 NS052819 / NS / NINDS NIH HHS / United States R01 HL112918 / HL / NHLBI NIH HHS / United States R01 MH118934 / MH / NIMH NIH HHS / United States R01 DA029122 / DA / NIDA NIH HHS / United States |