{"doi":"10.1172/jci.insight.150698","title":"Scn2a severe hypomorphic mutation decreases excitatory synaptic input and causes autism-associated behaviors","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.","journal":"JCI Insight","year":2021,"id":167391,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":32,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.937,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":440208,"name":"Charlotte C. Bavley","orcid":"0000-0001-7273-7392","position":1,"is_corresponding":false},{"id":72613,"name":"Anfei Li","orcid":"0000-0002-5124-7068","position":2,"is_corresponding":false},{"id":322851,"name":"Rebecca Jones","orcid":"0000-0001-6099-0171","position":3,"is_corresponding":false},{"id":440211,"name":"Jonathan Hackett","orcid":"0000-0003-4965-2045","position":4,"is_corresponding":false},{"id":332236,"name":"Yared Bayleyen","orcid":"0000-0001-7553-8516","position":5,"is_corresponding":false},{"id":72619,"name":"Francis S. Lee","orcid":"0000-0002-7108-9650","position":6,"is_corresponding":false},{"id":344892,"name":"Anjali M. Rajadhyaksha","orcid":"0000-0002-8399-5466","position":7,"is_corresponding":false},{"id":484277,"name":"Geoffrey S. Pitt","orcid":"0000-0003-2246-0289","position":8,"is_corresponding":false},{"id":228901,"name":"Hong‐Gang Wang","orcid":"0000-0003-0551-0571","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-18T23:45:58.359801Z","pmid":"34156984","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}