{"doi":"10.3389/fncel.2023.1175895","title":"Epilepsy in a mouse model of GNB1 encephalopathy arises from altered potassium (GIRK) channel signaling and is alleviated by a GIRK inhibitor","abstract":"De novo mutations in GNB1 , encoding the G β 1 subunit of G proteins, cause a neurodevelopmental disorder with global developmental delay and epilepsy, GNB1 encephalopathy. Here, we show that mice carrying a pathogenic mutation, K78R, recapitulate aspects of the disorder, including developmental delay and generalized seizures. Cultured mutant cortical neurons also display aberrant bursting activity on multi-electrode arrays. Strikingly, the antiepileptic drug ethosuximide (ETX) restores normal neuronal network behavior in vitro and suppresses spike-and-wave discharges (SWD) in vivo . ETX is a known blocker of T-type voltage-gated Ca 2+ channels and G protein-coupled potassium (GIRK) channels. Accordingly, we present evidence that K78R results in a gain-of-function (GoF) effect by increasing the activation of GIRK channels in cultured neurons and a heterologous model ( Xenopus oocytes)—an effect we show can be potently inhibited by ETX. This work implicates a GoF mechanism for GIRK channels in epilepsy, identifies a new mechanism of action for ETX in preventing seizures, and establishes this mouse model as a pre-clinical tool for translational research with predicative value for GNB1 encephalopathy.","journal":"Frontiers in Cellular Neuroscience","year":2023,"id":339724,"datarank":0.8047777854930667,"base_score":2.833213344056216,"endowment":2.833213344056216,"self_citation_contribution":0.42498200160843247,"citation_network_contribution":0.37979578388463425,"self_endowment_contribution":0.42498200160843247,"citer_contribution":0.37979578388463425,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":12,"citers_with_citation_signal":8,"citers_with_endowment":8,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9442,"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":732297,"name":"Haritha P. Reddy","orcid":"0000-0002-6280-6558","position":1,"is_corresponding":false},{"id":290330,"name":"Sabrina Petri","orcid":null,"position":2,"is_corresponding":false},{"id":288722,"name":"Damian J. Williams","orcid":"0000-0001-5891-6300","position":3,"is_corresponding":false},{"id":732301,"name":"Boris Shalomov","orcid":"0000-0002-1322-4906","position":4,"is_corresponding":false},{"id":40851,"name":"Ryan S. Dhindsa","orcid":"0000-0002-8965-0813","position":5,"is_corresponding":false},{"id":884557,"name":"Sahar Gelfman","orcid":"0000-0002-4727-7862","position":6,"is_corresponding":false},{"id":295017,"name":"Daniel Krizay","orcid":"0000-0002-6917-1217","position":7,"is_corresponding":false},{"id":1074171,"name":"Amal K. Bera","orcid":null,"position":8,"is_corresponding":false},{"id":558701,"name":"Mu Yang","orcid":"0000-0001-7084-029X","position":9,"is_corresponding":false},{"id":288724,"name":"Yueqing Peng","orcid":"0000-0002-3488-0670","position":10,"is_corresponding":false},{"id":577062,"name":"Christopher D. Makinson","orcid":"0000-0002-1427-8148","position":11,"is_corresponding":false},{"id":288726,"name":"Michael J. Boland","orcid":"0000-0001-5649-9603","position":12,"is_corresponding":false},{"id":96540,"name":"Wayne N. Frankel","orcid":"0000-0003-2241-5314","position":13,"is_corresponding":false},{"id":30756,"name":"David B. Goldstein","orcid":"0000-0002-1111-2820","position":14,"is_corresponding":false},{"id":732303,"name":"Nathan Dascal","orcid":"0000-0002-5397-4146","position":15,"is_corresponding":false},{"id":288717,"name":"Sophie Colombo","orcid":"0000-0001-8945-5631","position":0,"is_corresponding":true}],"reference_count":111,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:10:49.535464Z","pmid":"37275776","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":[]}