D1 Dopamine Receptor Activation Reduces GABAA Receptor Currents in Neostriatal Neurons Through a PKA/DARPP-32/PP1 Signaling Cascade

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Abstract
Dopamine is a critical determinant of neostriatal function, but its impact on intrastriatal GABAergic signaling is poorly understood. The role of D1 dopamine receptors in the regulation of postsynaptic GABAA receptors was characterized using whole cell voltage-clamp recordings in acutely isolated, rat neostriatal medium spiny neurons. Exogenous application of GABA evoked a rapidly desensitizing current that was blocked by bicuculline. Application of the D1 dopamine receptor agonist SKF 81297 reduced GABA-evoked currents in most medium spiny neurons. The D1 dopamine receptor antagonist SCH 23390 blocked the effect of SKF 81297. Membrane-permeant cAMP analogues mimicked the effect of D1 dopamine receptor stimulation, whereas an inhibitor of protein kinase A (PKA; Rp-8-chloroadenosine 3′,5′ cyclic monophosphothioate) attenuated the response to D1 dopamine receptor stimulation or cAMP analogues. Inhibitors of protein phosphatase 1/2A potentiated the modulation by cAMP analogues. Single-cell RT-PCR profiling revealed consistent expression of mRNA for the β1 subunit of the GABAAreceptor—a known substrate of PKA—in medium spiny neurons. Immunoprecipitation assays of radiolabeled proteins revealed that D1 dopamine receptor stimulation increased phosphorylation of GABAA receptor β1/β3 subunits. The D1dopamine receptor-induced phosphorylation of β1/β3 subunits was attenuated significantly in neostriata from DARPP-32 mutants. Voltage-clamp recordings corroborated these results, revealing that the efficacy of the D1 dopamine receptor modulation of GABAA currents was reduced in DARPP-32-deficient medium spiny neurons. These results argue that D1 dopamine receptor stimulation in neostriatal medium spiny neurons reduces postsynaptic GABAA receptor currents by activating a PKA/DARPP-32/protein phosphatase 1 signaling cascade targeting GABAA receptor β1 subunits.