Biphasic influence of sodium channel activation on neuronal structural plasticity

Abstract

Neuronal activity regulates neuronal development and synaptic plasticity through calcium‐dependent signaling pathways. We used brevetoxin‐2 (PbTx‐2), an activator of voltage‐gated sodium channels (VGSCs), to mimic the influence of neuronal activity. PbTx‐2‐ enhanced neurite outgrowth exhibited a biphasic concentration‐response profile (George et al., 2009) in murine cerebrocortical neurons. N‐methyl D‐aspartate (NMDA) also exhibited a biphasic concentration‐response profile on neurite outgrowth. We therefore hypothesized that the PbTx‐2 enhanced neuronal structural plasticity may be NMDA receptor (NMDAR) dependent. The influence of PbTx‐2 on dendritic arbor complexity and synaptogenesis also followed a biphasic pattern. These data are consistent with the hypothesis that PbTx‐2 enhanced neuronal plasticity involves NMDAR dependent signaling. PbTx‐2 exposure produced concentration‐dependent increments in intracellular [Ca2+] and [Na+]i. Pharmacological studies showed that PbTx‐2‐induced Ca2+ influx primarily involves VGSCs and NMDARs. Moreover, a subthreshold concentration of PbTx‐2 increased the maximum response for NMDA‐induced Ca2+influx. These results suggest that PbTx‐2 enhances NMDAR function. The ability of PbTx‐2 to activate VGSCs with attendant increments in [Na+]i represents a novel strategy to upregulate NMDAR signaling.