title: Rapid Increases in proBDNF after Pilocarpine-Induced Status Epilepticus in Mice Are Associated with Reduced proBDNF Cleavage Machinery.
abstract: 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 pathway that mediates a decrease in GABAA receptor 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 3 h after SE onset and remain elevated for 7 d. Immunohistochemistry studies indicate that seizure-induced BDNF localizes to all hippocampal subfields, predominantly in principal neurons and also in 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 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 h 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.
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045; Neuroscience Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045; Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: Ajay X
authors.identifier: 0000-0001-5249-3255
authors.initials: AX
authors.lastname: Thomas
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus , Aurora, Colorado 80045.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Cruz Del Angel
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045; Neuroscience Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: Marco I
authors.initials: MI
authors.lastname: Gonzalez
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045; Neuroscience Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carrel
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus , Aurora, Colorado 80045.
authors.forename: Jessica
authors.initials: J
authors.lastname: Carlsen
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus , Aurora, Colorado 80045.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Lam
authors.affiliation: Departments of Medicine, Hematology & Medical Oncology, Weil Cornell Medical College , New York, New York 10045.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Hempstead
authors.affiliation: Department of Pharmacology, Boston University School of Medicine , Boston, Massachusetts 02118.
authors.forename: Shelley J
authors.initials: SJ
authors.lastname: Russek
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045; Neuroscience Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045; Department of Neurology, Children's Hospital Colorado, Aurora, Colorado 80045.
authors.forename: Amy R
authors.identifier: 0000-0001-8727-9144
authors.initials: AR
authors.lastname: Brooks-Kayal
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D010862:Pilocarpine; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017395:Plasminogen Activator Inhibitor 1; D011498:Protein Precursors; C426674:brain-derived neurotrophic factor precursor; D010862:Pilocarpine
keywords: BDNF; PAI-1; ProBDNF; cleavage; epilepsy; tPA