Dopamine D₄ receptors modulate GABAergic signaling in pyramidal neurons of prefrontal cortex

Dopaminergic neurotransmission in the prefrontal cortex (PFC) plays an important role in regulating cognitive processes and emotional status. The dopamine D₄ receptor, which is highly enriched in the PFC, is one of the principal targets of antipsychotic drugs. To understand the cellular mechanisms and functional implications of D₄ receptors, we examined the impact of D₄ receptors in PFC pyramidal neurons on GABAergic inhibition, a key element in the regulation of "working memory." Application of the D₄ agonist N-(methyl)-4-(2-cyanophenyl) piperazinyl-3-methylbenzamide maleate caused a reversible decrease in postsynaptic GABA_A receptor currents; this effect was blocked by the D₄ antagonist 3-[(4-[4-chlorophenyl]piperazine-1-yl) methyl]-[¹H]-pyrrolo[2,3-b]pyridine but not by the D₂ antagonist sulpiride, suggesting mediation by D₄ receptors. Application of PD168077 also reduced the GABA_A receptor-mediated miniature IPSC amplitude in PFC pyramidal neurons recorded from slices. The D₄ modulation of GABA_A receptor currents was blocked by protein kinase A (PKA) activation and occluded by PKA inhibition. Inhibiting the catalytic activity of protein phosphatase 1 (PP1) also eliminated the effect of PD168077 on GABA_A currents. Furthermore, disrupting the association of the PKA/PP1 complex with its scaffold protein Yotiao significantly attenuated the D₄ modulation of GABA_A currents, suggesting that Yotiao-mediated targeting of PKA/PP1 to the vicinity of GABA_A receptors is required for the dopaminergic signaling. Together, our results show that activation of D₄ receptors in PFC pyramidal neurons inhibits GABA_A channel functions by regulating the PKA/PP1 signaling complex, which could underlie the D₄ modulation of PFC neuronal activity and the actions of antipsychotic drugs.