Abstract
Abstract only N‐methyl D‐aspartate receptor (NMDAR) activation stimulates calcium influx and brain‐derived neurotrophic factor (BDNF) – TrkB signaling. This pathway is implicated in activity‐dependent neuronal development and synaptic plasticity. Voltage‐gated sodium channel (VGSC) activators promote neuronal development by increasing [Na + ] i and upregulating NMDAR function. Here we tested the effect of the VGSC activator veratridine (VRT) on neurite outgrowth (NOG), synthesis and release of BDNF and TrkB activation in DIV1 cerebrocortical neurons. VRT enhanced NOG in a hormetic concentration‐response manner and this response was dependent on NMDAR and TrkB signaling. Inhibitors of NMDAR, TrkB, PI3K, and PLCγ inhibited VRT‐enhanced NOG. Acute treatment with VRT stimulated phosphorylation of TrkB and its downstream effectors Akt, mTOR, PLC, ERK1/2 and CREB. VRT increased BDNF synthesis and release in a concentration dependent manner; however, VRT stimulation of TrkB phosphorylation displayed a biphasic concentration‐response curve. VRT stimulation of BDNF synthesis required VGSCs and NMDARs. These data suggest that BDNF synthesis and release mediate VGSC activator‐enhanced NOG through activation of TrkB signaling. (NIH, R01NS053398)