Bidirectional influence of sodium channel activation on NMDA receptor-dependent cerebrocortical neuron structural plasticity.

Neuronal activity regulates brain development and synaptic plasticity through N-methyl-D-aspartate receptors (NMDARs) and calcium-dependent signaling pathways. Intracellular sodium ([Na(+)](i)) also exerts a regulatory influence on NMDAR channel activity, and [Na(+)](i) may, therefore, function as a signaling molecule. In an attempt to mimic the influence of neuronal activity on synaptic plasticity, we used brevetoxin-2 (PbTx-2), a voltage-gated sodium channel (VGSC) gating modifier, to manipulate [Na(+)](i) in cerebrocortical neurons. The acute application of PbTx-2 produced concentration-dependent increments in both intracellular [Na(+)] and [Ca(2+)]. Pharmacological evaluation showed that PbTx-2-induced Ca(2+) influx primarily involved VGSC activation and NMDAR-mediated entry. Additionally, PbTx-2 robustly potentiated NMDA-induced Ca(2+) influx. PbTx-2-exposed neurons showed enhanced neurite outgrowth, increased dendritic arbor complexity, and increased dendritic filopodia density. The appearance of spontaneous calcium oscillations, reflecting synchronous neuronal activity, was accelerated by PbTx-2 treatment. Parallel to this response, PbTx-2 increased cerebrocortical neuron synaptic density. PbTx-2 stimulation of neurite outgrowth, dendritic arborization, and synaptogenesis all exhibited bidirectional concentration-response profiles. This profile paralleled that of NMDA, which also produced bidirectional concentration-response profiles for neurite outgrowth and synaptogenesis. These data are consistent with the hypothesis that PbTx-2-enhanced neuronal plasticity involves NMDAR-dependent signaling. Our results demonstrate that PbTx-2 mimics activity-dependent neuronal structural plasticity in cerebrocortical neurons through an increase in [Na(+)](i), up-regulation of NMDAR function, and engagement of downstream Ca(2+)-dependent signaling pathways. These data suggest that VGSC gating modifiers may represent a pharmacologic strategy to regulate neuronal plasticity through NMDAR-dependent mechanisms.