Neuronal activity alters BDNF-TrkB signaling kinetics and downstream functions

Abstract

Differential kinetics of the same signaling pathway may elicit different cellular outcomes. Here we show that high-frequency neuronal activity converts BDNF-induced TrkB signaling from a transient to a sustained mode. A prior depolarization (15 mM KCl, 1 hour) resulted in a long-lasting (>24 hours) activation of TrkB receptor and its downstream signals which otherwise lasts less than an hour. The LTP-inducing theta-burst stimulation but not the LTD-inducing low-frequency stimulation also induced sustained activation of TrkB. This sustained signaling facilitated dendritic branching and rescued neuronal apoptosis induced by glutamate. The change in TrkB signaling kinetics is mediated by calcium elevation and CaMKII activation, leading to an increase in TrkB expression on the neuronal surface. Physical exercise also alters the kinetics of TrkB phosphorylation induced by exogenous BDNF. Sustained TrkB signaling may serve as a key mechanism underlying synergistic effects of neuronal activity and BDNF.