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.