Ribeiro Rodrigues, LeonorFonseca-Gomes, JoãoPaulo, Sara LViais, RicardoRibeiro, FilipaMiranda-Lourenço, CatarinaMouro, FranciscoBelo, Rita F.Ferreira, Catarina B.Tanqueiro, SaraFerreira-Manso, MafaldaUmemori, JuzohCastrén, EeroPaiva, Vítor H.Sebastião, Ana MAronica, EleonoraRainha Campos, AlexandreBentes, CarlaXapelli, SaraDiógenes, Maria José2025-05-292025-05-292025Pharmacol Res. 2025 May:215:1077071043-6618http://hdl.handle.net/10400.5/101103© 2025 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/)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.engBrain derived neurotrophic factor (BDNF)Status epilepticusTrkB-ICDSpontaneous seizuresCognitionjournal article10.1016/j.phrs.2025.1077071096-1186