Abstracts

Rationale: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates a wide variety of cell signaling pathways including pro- survival and cell death machinery in a receptor-specific manner. Previous studies in rat have demonstrated an increase in BDNF expression after status epilelepticus (SE), which activates inducible cAMP early repressor (ICER) transcription via Signal Transducer and Activator of Transcription 3 (STAT3) activation. ICER activation mediates a downstream decrease in the expression of the alpha 1 subunit of the GABAA receptor in the hippocampal dentate gyrus of rat. BDNF actions are mediated by TrkB and p75 neurotrophin receptor (NTR), but the specific receptor mediating BDNF induced JAK/STAT activation is not known. Recent studies have shown that modulation of p75NTR prevents BDNF-induced activation of the JAK/STAT pathway in rat cultured hippocampal neurons, suggesting that proBDNF, the high affinity ligand for p75NTR, may play a critical role. The goal of this project is to investigate the relative contribution of proBDNF signaling to the JAK/STAT pathway after seizure through the use of BDNF-tagged transgenic C57BL/6J mice. Methods: BDNF-HA tagged mice were subjected to a repetitive low-dose pilocarpine regimen to induce seizures and were then sacrificed acutely after seizure and levels of BDNF and phospho-STAT3 protein were probed via western blot. Results: In contrast to previous publications reporting that proBDNF does not increase until 72 hours after seizures, our studies indicate proBDNF levels in hippocampus were markedly increased within three hours of induction of status epilepticus. Preliminary immunohistochemistry studies indicate that seizure-induced BDNF increases occur primarily in hippocampal principal neurons after seizure. Conclusions: These studies suggest that proBDNF increases acutely following the onset of SE and provide the foundation to further investigate the role of proBDNF signaling in epileptogenesis.