TrkB signaling has a key role in survival in a model of Status Epilepticus

MONTROULL, LAURA; DANELON, VÍCTOR; MASCÓ, DANIEL HUGO

Rio de Janeiro

Congreso; 9th World Congress of the International Brain Research Organization (IBRO); 2015

International Brain Research Organization

Neurotrophins are secretory proteins that bind to target receptors influencing survival activity.Brain-Derived Neurotrophic Factor (BDNF) is initially synthesized as proBDNF that is cleaved to release the mature form. BDNF binds to TrkB leading to neuron survival and proBDNF interact with p75ntr leading to apoptosis (Teng et al, 2010). Many studies have demonstrated that seizures induce changes in the expression of NT, pro-NT and their receptors (Friedman 2000). We have previously shown that Status Epilepticus (SE) induced a rapid down-regulation of TrkB that precedes neuronal death in the CA1 and a switch among BDNF/TrkB to BDNF/p75ntr and proBDNF/p75ntr binding (Unsain et al, 2008). We hypothesize that the decrease in TrkB signaling has a key role in the development of neuronal death. To test this, we used in vitro and in vivo models of SE. We found that 3h of neuronal hyperactivation in a co-culture of hippocampal neurons and astrocytes induces neuronal death 24h after SE. When TrkB-Fc (a BDNF scavenger) was added to the co-culture immediately after the excitotoxic insult, we found an increase in neuronal death. Similar results were found when TrkB-Fc was injected into the hippocampal CA1 immediately after SE. Also we found that TrkB-Fc prevents the decrease in TrkB levels, but induces a decrease in phospho-TrkB. To test whether the increase in neuronal death was due to proBDNF/p75ntr signaling in absence of TrkB signaling, we infused TrkB-Fc and at the same time, anti proBDNF. The interaction of proBDNF with p75ntr was no affected but we found an important decrease in neuronal death in the infused hippocampus as compared with non-infused hippocampus. These results suggest that massive released of BDNF after SE induces a decrease of TrkB levels and this scenario could facilitate proBDNF binding to p75ntr leading to neuronal death.