To die or to not die? The fight between TrkB and p75ntr signaling

MONTROULL L; DANELON V; ZAMPONI E; HELGUERA P; MASCO D

Huerta Grande

Congreso; XXIX Reunión anual de la Sociedad Argentina de Investigación en Neurociencias (SAN); 2014

Sociedad Argentina de Investigación en Neurociencias (SAN)

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 BDNF. BDNF binds to TrkB leading to neuron survival and proBDNF interact with p75ntr leading to apoptosis. We showed that 3h of neuronal hyperactivation in a co-culture of hippocampal neurons and astrocytes induces neuronal death. Also we demonstrated that Status Epilepticus (SE) in vivo induced death through a decrease in TrkB expression and a switch among BDNF/TrkB to BDNF/p75ntr and proBDNF/p75ntr binding. We hypothesize that this phenomenon has a key role in the development of neuronal death. To test this we added to the co-culture TrkB-Fc immediately after the excitotoxic insult and we found an increase in neuronal death. To test whether the neuronal death was due to proBDNF/ p75ntr signaling in absence of TrkB signaling, we administrated unilaterally TrkB-Fc and anti proBDNF in the hippocampal CA1 immediately after SE. Neuronal damage was assessed by FJB. We found an important decrease in the number of FJB positive cells in the infused hippocampus as compared with non-infused hippocampus. Since it has been suggested that proNT signaling is able to suppress Trkmediated survival signaling, our next goal is to determinate whether proBDNF is able to suppress TrkB signaling. To test this we are going to overexpress TrkB in the hippocampal CA1 using lentivirus system before SE.