Sodium channel activator‐induced neuronal development is NMDA receptor dependent and involves a Ca2+/calmodulin kinase (CaMK)‐CREB‐BDNF signaling pathway

Abstract

Many aspects of activity‐dependent neuronal development such as dendritic arborization, spinogenesis and synaptogenesis are mediated through NMDA receptor [NMDAR]‐dependent Ca2+ signaling mechanisms. Brevetoxin‐2 (PbTx‐2), an activator of voltage‐gated sodium channels, mimics activity‐dependent control of neuronal development by elevating intracellular sodium levels and augmenting NMDAR function. PbTx‐2 enhanced cerebrocortical neuron spinogenesis and synapse density. Morphological analysis showed that PbTx‐2 enhanced spinogenesis by stimulating dendritic filopodia formation. Pharmacological evaluation showed that the PbTx‐2 induced neuronal plasticity was mediated by signaling mechanisms downstream of CaMKK. PbTx‐2 exposure produced phosphorylation and activation of CaMKI (Thr177) and CaMKII (Thr286). PbTx‐2 also induced ErK 1/2, but not Akt, phosphorylation. CREB is known to be an activity‐regulated transcription factor, and PbTx‐2 exposure increased CREB phosphorylation at Ser‐133. Assessment of brain derived neurotrophic factor (BDNF) transcription with RT‐PCR demonstrated that BDNF mRNA expression level increased in a time and PbTx‐2 concentration dependent manner. These findings suggest that the sodium channel activator influence on neuronal developmental involves NMDAR‐mediated CaMK signaling with downstream activation of CREB‐dependent transcription of BDNF.