{"doi":"10.1093/braincomms/fcae327","title":"Enhanced Fyn-tau and NR2B-PSD95 interactions in epileptic foci in experimental models and human epilepsy","abstract":"Abstract Epilepsy and Alzheimer’s disease share some common pathologies such as neurodegeneration, seizures and impaired cognition. However, the molecular mechanisms of these changes are still largely unknown. Fyn, a Src-family non-receptor tyrosine kinase (SFK), and its interaction with tau in mediating brain pathology in epilepsy and Alzheimer’s disease can be a potential therapeutic target for disease modification. Although Fyn and tau pathology occurs in both Alzheimer’s disease and epilepsy, the dynamics of Fyn-tau and PSD95-NR2B interactions affected by seizures and their impact on brain pathology in epilepsy have not been investigated. In this study, we demonstrate a significant increase of Fyn-tau interactions following seizure induction by kainate in both acute and chronic rodent models and in human epilepsy. In the early phase of epileptogenesis, we show increased Fyn/tau/NR2B/PSD95/neuronal nitric oxide synthase complexes after status epilepticus and a postsynaptic increase of phosphorylated tau (pY18 and AT8), Fyn (pSFK-Y416), NMDAR (pNR2B-Y1472) and neuronal nitric oxide synthase. Hippocampal proximity ligation assay and co-immunoprecipitation revealed a sustained increase of Fyn-tau and NR2B-PSD95 complexes/binding in rat chronic epilepsy at 3 months post-status epilepticus. Enhanced Fyn-tau complexes strongly correlated with the frequency of spontaneously recurring convulsive seizures and epileptiform spikes in the chronic epilepsy model. In human epileptic brains, we also identified increased Fyn-tau and NR2B-PSD95 complexes, tau phosphorylation (pY18 and AT8) and Fyn activation (pSFK-Y416), implying the translational and therapeutic potential of these molecular interactions. In tau knockout mice and in rats treated with a Fyn/SFK inhibitor saracatinib, we found a significant reduction of phosphorylated Fyn, tau (AT8 in saracatinib-treated), NR2B and neuronal nitric oxide synthase and their interactions (Fyn-tau and NR2B-PSD95 in saracatinib-treated group; NR2B-PSD95 in tau knockout group). The reduction of Fyn-tau and NR2B-PSD95 interactions in the saracatinib-treated group, in contrast to the vehicle-treated group, correlated with the modification in seizure progression in the rat chronic epilepsy model. These findings from animal models and human epilepsy provide evidence for the role of Fyn-tau and NR2B-PSD95 interactions in seizure-induced brain pathology and suggest that blocking such interactions could modify the progression of epilepsy.","journal":"Brain Communications","year":2024,"id":431236,"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":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9494,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":804524,"name":"Nikhil Rao","orcid":"0000-0003-0281-932X","position":1,"is_corresponding":false},{"id":1235537,"name":"Cara Gardner","orcid":null,"position":2,"is_corresponding":false},{"id":335100,"name":"Guanghao Liu","orcid":"0000-0001-8386-5410","position":3,"is_corresponding":false},{"id":1235538,"name":"Jordan Trommater","orcid":null,"position":4,"is_corresponding":false},{"id":1235539,"name":"Michael Bunney","orcid":null,"position":5,"is_corresponding":false},{"id":705922,"name":"Meghan Gage","orcid":null,"position":6,"is_corresponding":false},{"id":285420,"name":"Alexander G. Bassuk","orcid":"0000-0002-4067-2157","position":7,"is_corresponding":false},{"id":343798,"name":"Marco M. Hefti","orcid":"0000-0002-3127-4528","position":8,"is_corresponding":false},{"id":331238,"name":"Gloria Lee","orcid":"0000-0002-8633-1534","position":9,"is_corresponding":false},{"id":335101,"name":"Thimmasettappa Thippeswamy","orcid":"0000-0002-9326-1896","position":10,"is_corresponding":false},{"id":335098,"name":"Marson Putra","orcid":"0000-0002-4929-4498","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-19T01:59:25.642507Z","pmid":"39355003","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":[]}