Neuronal activity alters BDNF-TrkB signaling kinetics and downstream functions.

Differential kinetics of the same signaling pathway might elicit different cellular outcomes. Here, we show that high-frequency neuronal activity converts BDNF-induced TrkB (also known as NTRK2) 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 the TrkB receptor and its downstream signaling, which otherwise lasts less than an hour. The long-term potentiation (LTP)-inducing theta-burst stimulation but not the long-term depression (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 Ca(2+) 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 might serve as a key mechanism underlying the synergistic effects of neuronal activity and BDNF.