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

George, Joju, Baden, Daniel G., Gerwick, William H., Murray, Thomas F.
Proceedings of the National Academy of Sciences of the United States of America 2012 v.109 no.48 pp. 19840-19845
brain, calcium, neurites, neuroplasticity, pseudopodia, receptors, signal transduction, sodium, sodium channels, synaptogenesis
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.