{"doi":"10.1016/j.phrs.2025.107707","title":"Cleavage of the TrkB-FL receptor during epileptogenesis: insights from a kainic acid-induced model of epilepsy and human samples","abstract":"Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival, differentiation, and plasticity. In epilepsy, BDNF exhibits a dual role, exerting both antiepileptic and pro-epileptic effects. The cleavage of its main receptor, full-length tropomyosin-related kinase B (TrkB-FL), was suggested to occur in status epilepticus (SE) in vitro. Moreover, under excitotoxic conditions, TrkB-FL was found to be cleaved, resulting in the formation of a new intracellular fragment, TrkB-ICD. Thus, we hypothesized that TrkB-FL cleavage and TrkB-ICD formation could represent an uncovered mechanism in epilepsy. We used a rat model of mesial temporal lobe epilepsy (mTLE) induced by kainic acid (KA) to investigate TrkB-FL cleavage and TrkB-ICD formation during SE (∼3 h after KA) and established epilepsy (EE) (4–5 weeks after KA). Animals treated with 10 mg/kg of KA exhibited TrkB-FL cleavage during SE, with hippocampal levels of TrkB-FL and TrkB-ICD correlating with seizure severity. Notably, TrkB-FL cleavage and TrkB-ICD formation were also detected in animals with EE, which exhibited spontaneous recurrent convulsive seizures, neuronal death, mossy fiber sprouting, and long-term memory impairment. Importantly, hippocampal samples from patients with refractory epilepsy also showed TrkB-FL cleavage with increased TrkB-ICD levels. Additionally, lentiviral-mediated overexpression of TrkB-ICD in the hippocampus of healthy mice and rats resulted in long-term memory impairment. Our findings suggest that TrkB-FL cleavage and the subsequent TrkB-ICD production occur throughout epileptogenesis, with the extent of cleavage correlating positively with seizure occurrence. Moreover, we found that TrkB-ICD overexpression impairs memory. This work uncovers a novel mechanism in epileptogenesis that could serve as a potential therapeutic target in mTLE, with implications for preserving cognitive function. • Administration of 10 mg/kg of KA induces stage 5 seizures in 55.2 % of animals. • KA-induced stage 5 seizures promote TrkB-FL cleavage and TrkB-ICD formation. • Animals with established epilepsy present TrkB-FL cleavage and TrkB-ICD formation. • Hippocampal samples from refractory epilepsy patients display TrkB-FL cleavage. • Overexpression of TrkB-ICD leads to memory impairment in healthy rodents.","journal":"Pharmacological Research","year":2025,"id":532107,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9505,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1412867,"name":"João Fonseca‐Gomes","orcid":"0000-0001-7915-3517","position":1,"is_corresponding":false},{"id":1412868,"name":"Sara L. Paulo","orcid":"0000-0001-7668-2173","position":2,"is_corresponding":false},{"id":469238,"name":"Ricardo Viais","orcid":"0000-0002-8146-3693","position":3,"is_corresponding":false},{"id":1412869,"name":"Filipa F. Ribeiro","orcid":"0000-0002-4006-7328","position":4,"is_corresponding":false},{"id":1412870,"name":"Catarina Miranda‐Lourenço","orcid":"0000-0002-9633-7999","position":5,"is_corresponding":false},{"id":1412871,"name":"Francisco M. Mouro","orcid":"0000-0002-7141-8418","position":6,"is_corresponding":false},{"id":1412872,"name":"Rita F. Belo","orcid":"0000-0002-4553-3455","position":7,"is_corresponding":false},{"id":588068,"name":"Catarina B. Ferreira","orcid":"0000-0002-2538-1650","position":8,"is_corresponding":false},{"id":1412873,"name":"Sara R. Tanqueiro","orcid":"0000-0002-9151-7149","position":9,"is_corresponding":false},{"id":1412874,"name":"Mafalda Ferreira-Manso","orcid":"0000-0001-5074-8154","position":10,"is_corresponding":false},{"id":1412875,"name":"Juzoh Umemori","orcid":"0000-0003-2595-7362","position":11,"is_corresponding":false},{"id":615790,"name":"Eero Ċastrén","orcid":"0000-0002-1402-2791","position":12,"is_corresponding":false},{"id":1269574,"name":"Vítor H. Paiva","orcid":"0000-0001-6368-9579","position":13,"is_corresponding":false},{"id":290981,"name":"Ana M. 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