Serotonin receptor activation inhibits sodium current and dendritic excitability in prefrontal cortex via a protein kinase C-dependent mechanism

The serotonin (5-HT) innervation of the prefrontal cortex (PFC) exerts a powerful modulatory influence on neuronal activity in this cortical region, although the mechanisms through which 5-HT modulates cellular activity are unclear. Voltage-dependent Na⁺ channels are one potential target of 5-HT receptor signaling that have wide-ranging effects on activity. Molecular and electrophysiological studies were used to test this potential linkage. Single cell RT-PCR profiling revealed that the vast majority of pyramidal neurons expressed detectable levels of 5-HT_2a and/or 5-HT_2c receptor mRNA with half of the cells expressing both mRNAs. Whole-cell voltage-clamp recordings of dissociated pyramidal neurons showed that 5-HT_2a/c receptor activation reduced rapidly inactivating Na⁺ currents by reducing maximal current amplitude and shifting fast inactivation voltage dependence. These effects were mediated by G_q activation of phospholipase C, leading to activation of protein kinase C (PKC). 5-HT_2a/c receptor stimulation also reduced the amplitude of persistent Na⁺ current without altering its activation voltage dependence. This modulation was also mediated by PKC. Although 5-HT_2a,c receptor activation did not affect somatic action potentials of layer V pyramidal neurons in PFC slices, it did reduce the amplitude of action potentials back-propagating into the apical dendrite. These findings show that 5-HT_2a,c receptor activation reduces dendritic excitability and may negatively modulate activity-dependent dendritic synaptic plasticity.