{"doi":"10.7302/8623","title":"Sodium Channel Scn8a as a Target for Antiepileptic Therapy","abstract":"The voltage-gated sodium channel Nav1.6 is a key regulator of neuronal excitability. Gain-of-function variants of SCN8A, the gene encoding Nav1.6, cause developmental and epileptic encephalopathy (DEE). SCN8A-DEE is characterized by drug-resistant seizures, movement disorders, and intellectual disability. We hypothesized that reducing expression of SCN8A would compensate for gain-of-function mutations. We developed an antisense oligonucleotide (ASO) that reduces expression of mouse Scn8a transcript. In SCN8A-DEE mice, neonatal administration of the Scn8a ASO delayed seizure onset and prolonged lifespan. However, people with SCN8A-DEE can only be treated after they begin to have seizures and receive a diagnosis. I therefore also administered the Scn8a ASO after the onset of seizures. The ASO reduced seizure frequency and prolonged survival from less than two months to more than one year after seizure onset. Due to its important role in the generation of action potentials, we hypothesized that reducing SCN8A expression could also be therapeutic in epilepsy caused by mutation of other genes. I administered the Scn8a ASO to epilepsy models caused by mutation of the sodium channel gene Scn1a, the potassium channel genes Kcna1 and Kcnq2, and the synaptic protein LGI1. The Scn8a ASO prolonged survival in all four models. Notably, the Scn1a mutant mice were completely rescued by a single, neonatal dose. I also tested reduction of potassium channel gene Kcnt1 in Scn1a and Scn8a mutants. The Kcnt1 ASO significantly prolonged survival of both models, though to a lesser extent than the Scn8a ASO. These results suggest that targeting key ion channel genes, including Scn8a and Kcnt1, may be a generalizable treatment for epilepsies of diverse etiologies. Despite the prominent role of ion channel genes in causing epilepsy, little is known about the transcriptional consequences of ion channel mutations. I performed single-nucleus RNA-sequencing on the hippocampus of Scn8a mutant mice. Before the onset of seizures, I detected few transcriptional changes within any cell type. After ten weeks of chronic seizures, dentate gyrus granule cells exhibited the most transcriptional changes, suggesting that seizures may specifically affect this cell type. I also detected expression of the voltage-gated sodium channels in oligodendrocyte precursor cells and a possible increase in the number of hippocampal oligodendrocytes in the Scn8a mutant mice, which may point to a role for sodium channels in oligodendrocyte differentiation. My results suggest that oligodendrocytes and dentate gyrus granule cells may play a role in the pathology of SCN8A-DEE.","journal":"Deep Blue (University of Michigan)","year":2023,"id":411724,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9683,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":262354,"name":"Sophie F. Hill","orcid":"0000-0002-8331-9812","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T01:21:42.971455Z","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":[]}