TY - JOUR T1 - Rapid increases in proBDNF after pilocarpine-induced status epilepticus in mice are associated with reduced proBDNF cleavage machinery JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0020-15.2016 SP - ENEURO.0020-15.2016 AU - Ajay X. Thomas AU - Yasmin Cruz Del Angel AU - Marco I. Gonzalez AU - Andrew J. Carrel AU - Jessica Carlsen AU - Philip M. Lam AU - Barbara L. Hempstead AU - Shelley. J. Russek AU - Amy R. Brooks-Kayal Y1 - 2016/02/10 UR - http://www.eneuro.org/content/early/2016/02/09/ENEURO.0020-15.2016.abstract N2 - Brain-derived neurotrophic factor (BDNF) levels are elevated after status epilepticus (SE), leading to activation of multiple signaling pathways, including the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway that mediates a decrease in GABAA receptor (GABAAR) α1- subunits in the hippocampus (Lund et al., 2008). While BDNF can signal via its pro- or mature form, the relative contribution of these forms to signaling after SE is not fully known. In the current study, we investigate changes in proBDNF levels acutely after SE in C57BL/6J mice. In contrast to previous reports (Unsain et al., 2008; Volosin et al., 2008; VonDran et al., 2014), our studies found that levels of proBDNF in the hippocampus are markedly elevated as early as three hours after SE onset and remain elevated for seven days. Immunohistochemistry studies indicate that seizure-induced BDNF localizes to all hippocampal subfields, predominantly in principal neurons and also astrocytes. Analysis of the proteolytic machinery that cleaves proBDNF to produce mature BDNF demonstrates that acutely after SE there is a decrease in tissue plasminogen activator (tPA) and an increase in plasminogen activator inhibitor-1 (PAI-1), an inhibitor of extracellular and intracellular cleavage, which normalizes over the first week after SE. In vitro treatment of hippocampal slices from animals 24 hours after SE with a PAI-1 inhibitor reduces proBDNF levels. These findings suggest that rapid proBDNF increases following SE are due in part to reduced cleavage, and that proBDNF may be part of the initial neurotrophin response driving intracellular signaling during the acute phase of epileptogenesis.Significance Statement: The studies reported here are the first to demonstrate acute changes in the expression of proBDNF within three hours of onset of status epilpticus (SE) onset that occur within principle cells and glia in all hippocampal subfields. We further found evidence that reduced expression of tPA, part of the extracellular proteolytic cascade, and increased expression of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of extracellular and intracellular cleavage, may contribute to reduced proBDNF cleavage and elevations in proBDNF levels. These findings suggest that proBDNF may be part of the initial neurotrophin response driving intracellular signaling acutely after SE and during the earliest phase of epileptogenesis. ER -