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 GABA A receptor ␣1 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.Key words: BDNF; cleavage; epilepsy; PAI-1; ProBDNF; tPA Significance StatementThe studies reported here are the first to demonstrate acute changes in the expression of proBDNF within 3 h of the onset of status epilpticus (SE) that occur within principle cells and glia in all hippocampal subfields. We further found evidence that reduced expression of tissue plasminogen activator, part of the extracellular proteolytic cascade, and increased expression of plasminogen activator inhibitor-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.

Blockade of p75 Neurotrophin Receptor Reverses Irritability and Anxiety-Related Behaviors in a Rat Model of Status Epilepticus

“…In line with previous investigations in epileptic rats [42,[44][45][46] , we demonstrated here the up-regulation of mRNA expressions of p75NTR and pro-NGF in a rat pilocarpine-induced SE model, which in turn is associated with the elevated level of aggressive behavior.…”

Transcriptomic analysis of the BDNF-induced JAK/STAT pathway in neurons: a window into epilepsy-associated gene expression

“…p75NTR levels are elevated after SE in animals and increased activation by proBDNF, like mature BDNF, increases susceptibility to seizures (13,14). Interestingly, our labs have shown that increased synthesis of proBDNF, and not mature BDNF, is the first response of the injured brain in the pilocarpine (PILO) model of epilepsy prior to SEinduced increases of p75NTR (15). This finding suggests that high levels of proBDNF may exert their effects through TrkB rather than p75NTR.…”

Protective Role of L-3-n-Butylphthalide in Cognitive Function and Dysthymic Disorders in Mouse With Chronic Epilepsy

“…Treatment with antidepressant or antianxiety drugs can restore Bdnf mRNA level in stress-induced model ( Smith et al, 1995 ; Kozisek et al, 2008 ). Although it has been reported that BDNF expression was enhanced in pilocarpine-induced SE ( Thomas et al, 2016 ), BDNF has also been found decreased in patients with chronic temporal lobe epilepsy (TLE) and in animal model of chronic cyclothiazide seizure ( Kong and Cheng, 2014 ; Chen et al, 2016 ). Besides, Xiang et al (2014) pointed out that NBP alleviated cognitive dysfunction in APP mice by BDNF/TrkB/PI3K/AKT pathway.…”