Serotonin Receptor Activation Inhibits Sodium Current and Dendritic Excitability in Prefrontal Cortex via a Protein Kinase C-Dependent Mechanism

Abstract

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-HT2a and/or 5-HT2c receptor mRNA with half of the cells expressing both mRNAs. Whole-cell voltage-clamp recordings of dissociated pyramidal neurons showed that 5-HT2a/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-HT2a/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 backpropagating into the apical dendrite. These findings show that 5-HT2a,c receptor activation reduces dendritic excitability and may negatively modulate activity-dependent dendritic synaptic plasticity.

Administration of SCH 23390 into the Medial Prefrontal Cortex Blocks the Expression of MDMA-Induced Behavioral Sensitization in Rats: An Effect Mediated by 5-HT2C Receptor Stimulation and not by D1 Receptor Blockade

“…Thus, and although taken into account in very few studies, SCH 23390 also stimulates 5-HT 2C receptors, exhibiting a fairly good affinity for these receptors (K i E0.3 nM for D1 receptors vs K i E6.3 nM for 5-HT 2C receptors; Briggs et al, 1991;Bourne, 2001;Millan et al, 2001). Iontophoretic application of 5-HT ligands suppresses spontaneous firing of PFC neurons in a 5-HT 2C receptor-dependent manner (Bergqvist et al, 1999), suggesting that the 5-HT 2C receptor limits the excitability of cortical pyramidal neurons (Carr et al, 2002). Therefore, it could be thought that SCH 23390 is capable of blocking MDMA sensitization by stimulating mPFC 5-HT 2C receptors.…”

Endogenous Activation of Serotonin-2A Receptors Is Required for Respiratory Rhythm GenerationIn Vitro

“…A modulation of both the transient and the persistent sodium current by 5-HT 2A receptors has been demonstrated in the prefrontal cortex (Carr et al, 2002).…”

Serotonin as a Modulator of Glutamate- and GABA-Mediated Neurotransmission: Implications in Physiological Functions and in Pathology

“…The final effect on membrane potential is hyperpolarizing for 5-HT 1A receptors and depolarizing for most other subtypes, with a fast depolarization mediated by 5-HT 3 receptors and a slow depolarization mediated by 5-HT 2A-B , 5-HT 4 and 5-HT 7 receptors. 5-HT 2C were shown to exert either hyperpolarizing [25,37] or depolarizing effects [48,190] in distinct areas.…”