Serotonin receptors modulate GABAA receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons

Abstract

Serotonergic neurotransmission in prefrontal cortex (PFC) has long been known to play a key role in regulating emotion and cognition under normal and pathological conditions. However, the cellular mechanisms by which this regulation occurs are unclear. In this study, we examined the impact of serotonin on GABAA receptor channels in PFC pyramidal neurons using combined patch-clamp recording, biochemical, and molecular approaches. Application of serotonin produced a reduction of postsynaptic GABAA receptor currents. Although multiple 5-HT receptors were coexpressed in PFC pyramidal neurons, the serotonergic modulation of GABA-evoked currents was mimicked by the 5-HT2-class agonist (-)-2,5-dimethoxy-4-iodoamphetamine and blocked by 5-HT2 antagonists risperidone and ketanserin, indicating the mediation by 5-HT2 receptors. Inhibiting phospholipase C blocked the 5-HT2 inhibition of GABAA currents, as did dialysis with protein kinase C (PKC) inhibitory peptide. Moreover, activation of 5-HT2 receptors in PFC slices increased the in vitro kinase activity of PKC toward GABAA receptor γ2 subunits. Disrupting the interaction of PKC with its anchoring protein RACK1 (receptor for activated C kinase) eliminated the 5-HT2 modulation of GABAA currents, suggesting that RACK1-mediated targeting of PKC to the vicinity of GABAA receptors is required for the serotonergic signaling. Together, our results show that activation of 5-HT2 receptors in PFC pyramidal neurons inhibits GABAA currents through phosphorylation of GABAA receptors by the activation of anchored PKC. The suppression of GABAergic signaling provides a novel mechanism for serotonergic modulation of PFC neuronal activity, which may underlie the actions of many antidepressant drugs.