{"doi":"10.1101/2021.02.02.429384","title":"Severe deficiency of voltage-gated sodium channel Na <sub>V</sub> 1.2 elevates neuronal excitability in adult mice","abstract":"Abstract Scn2a encodes voltage-gated sodium channel Na V 1.2, which mediates neuronal firing. The current paradigm suggests that Na V 1.2 gain-of-function variants enhance neuronal excitability resulting in epilepsy, whereas Na V 1.2 deficiency impairs neuronal excitability contributing to autism. In this paradigm, however, why about a third of patients with Na V 1.2 deficiency still develop seizures remains a mystery. Here we challenge the conventional wisdom, reporting that neuronal excitability is increased with severe Na V 1.2 deficiency. Using a unique gene-trap knockout mouse model of Scn2a , we found enhanced intrinsic excitabilities of principal neurons in the cortico-striatal circuit, known to be involved in Scn2a -related seizures. This increased excitability is autonomous, and is reversible by genetic restoration of Scn2a expression in adult mice. Mechanistic investigation reveals a compensatory downregulation of potassium channels including K V 1.1, which could be targeted to alleviate neuronal hyperexcitability. Our unexpected findings may explain Na V 1.2 deficiency-related epileptic seizures in humans and provide molecular targets for potential interventions. TEASER Severe Na V 1.2 deficiency results in neuronal hyperexcitability via the compensatory downregulation of potassium channels. HIGHLIGHTS Severe Na V 1.2 deficiency results in enhanced excitability of medium spiny neurons (MSNs) and pyramidal neurons in adult mice; Increased neuronal excitability in MSNs is accompanied by elevated voltage threshold; Na V 1.2 deficiency-related hyperexcitability is reversible with the restoration of Scn2a expression, and is autonomous; The expression of the K V 1.1 channel has a compensatory reduction in neurons with Na V 1.2 deficiency, and KV channels openers normalize the neuronal excitability; The enhanced excitability in brain slices translates to elevated in vivo firing commonly associated with seizures.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":218395,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9585,"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":337746,"name":"Xiaoling Chen","orcid":"0000-0002-2271-1140","position":1,"is_corresponding":false},{"id":337742,"name":"Muriel Eaton","orcid":"0000-0002-8634-1214","position":2,"is_corresponding":false},{"id":816179,"name":"Shirong Lai","orcid":"0009-0008-7615-0861","position":3,"is_corresponding":false},{"id":631784,"name":"Anthony Park","orcid":"0000-0002-5686-839X","position":4,"is_corresponding":false},{"id":633268,"name":"Talha S. Ahmad","orcid":null,"position":5,"is_corresponding":false},{"id":337749,"name":"Jiaxiang Wu","orcid":"0000-0002-1474-3820","position":6,"is_corresponding":false},{"id":337744,"name":"Zhixiong Ma","orcid":"0000-0002-0088-8041","position":7,"is_corresponding":false},{"id":337748,"name":"Zhefu Que","orcid":"0000-0002-1358-0660","position":8,"is_corresponding":false},{"id":338576,"name":"Ji Hea Lee","orcid":null,"position":9,"is_corresponding":false},{"id":337747,"name":"Tiange Xiao","orcid":"0000-0001-8579-832X","position":10,"is_corresponding":false},{"id":633269,"name":"Yuansong Li","orcid":null,"position":11,"is_corresponding":false},{"id":631785,"name":"Yujia Wang","orcid":"0000-0002-5096-1147","position":12,"is_corresponding":false},{"id":633270,"name":"Maria I. Olivero-Acosta","orcid":null,"position":13,"is_corresponding":false},{"id":283888,"name":"James A. Schaber","orcid":null,"position":14,"is_corresponding":false},{"id":474920,"name":"Krishna Jayant","orcid":"0000-0003-4353-6123","position":15,"is_corresponding":false},{"id":337750,"name":"Zhuo Huang","orcid":"0000-0001-9198-4778","position":16,"is_corresponding":false},{"id":338751,"name":"Nadia A. Lanman","orcid":"0000-0002-1819-7070","position":17,"is_corresponding":false},{"id":337751,"name":"William C. Skarnes","orcid":"0000-0002-8334-3329","position":18,"is_corresponding":false},{"id":337753,"name":"Yang Yang","orcid":"0000-0001-6417-3654","position":19,"is_corresponding":false},{"id":337743,"name":"Jingliang Zhang","orcid":"0000-0002-2903-1287","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-18T23:53:29.626149Z","pmid":null,"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":[]}