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The Journal of Neuroscience, September 1, 2001, 21(17):6502-6511

Serotonin Receptors Modulate GABA_A Receptor Channels through Activation of Anchored Protein Kinase C in Prefrontal Cortical Neurons

Jian Feng, Xiang Cai, Jinghui Zhao, and Zhen Yan

Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York 14214

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 GABA_A receptor channels in PFC pyramidal neurons using combined patch-clamp recording, biochemical, and molecular approaches. Application of serotonin produced a reduction of postsynaptic GABA_A 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 GABA_A 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 GABA_A receptor 2 subunits. Disrupting the interaction of PKC with its anchoring protein RACK1 (receptor for activated C kinase) eliminated the 5-HT₂ modulation of GABA_A currents, suggesting that RACK1-mediated targeting of PKC to the vicinity of GABA_A receptors is required for the serotonergic signaling. Together, our results show that activation of 5-HT₂ receptors in PFC pyramidal neurons inhibits GABA_A currents through phosphorylation of GABA_A 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.

Key words: prefrontal cortex; serotonin receptors; GABA_A receptors; phosphorylation; anchoring proteins; RACK1; patch-clamp; single-cell mRNA profiling

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21176502-10$05.00/0

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