Depolarization of PC12 cells induces neurite outgrowth and enhances nerve growth factor-induced neurite outgrowth in rats.

Synaptic plasticity is clearly controlled by synaptic activity and by neurotrophin-dependent signaling. We have previously hypothesized that synaptic activity modulates concomitant neurotrophin receptor signaling, thereby integrating the activity state of a synapse with the state of neurotrophic support available at the synapse. Herein we present evidence in support of this hypothesis. Using PC12 cells as a model of the presynaptic element, we show that depolarization increases TrkA tyrosine phosphorylation in response to nerve growth factor (NGF). Moreover, we show that depolarization alone is sufficient to induce the tyrosine phosphorylation of TrkA. These findings are functionally relevant, as evidenced by our observation that depolarization alone induces neurite outgrowth, and that depolarization dramatically enhances neurite outgrowth in response to NGF, especially in primed PC12 cells. We conclude that normal synaptic function may depend upon the integration of synaptic activity and activity-dependent neurotrophin release and signaling, and that these findings have potential relevance to neural repair.