Unexpected contributions of striatal projection neurons coexpressing dopamine D1 and D2 receptors in balancing motor control

Abstract The central function of the striatum and its dopaminergic (DA) afferents in motor control and the integration of cognitive and emotional processes is commonly explained by the two striatal efferent pathways characterized by striatal projection neurons (SPNs) expressing DA D1 receptors and D2 receptors (D1-SPNs and D2-SPNs), without regard to SPNs coexpressing both receptors (D1/D2-SPNs). We developed an approach that enables the targeting of these hybrid SPNs and demonstrated that although these SPNs are less abundant, they play a major role in guiding the motor function of the other two main populations. D1/D2-SPNs project exclusively to the external globus pallidus (GPe) and have specific electrophysiological features with distinctive integration of DA signals. Optogenetic stimulation and loss-of-function experiments indicated that D1/D2-SPNs potentiate the prokinetic and antikinetic functions of D1-SPNs and D2-SPNs, respectively, and restrain the integrated motor response to psychostimulants. Overall, our findings demonstrate the essential role of this third unacknowledged population of D1/D2 coexpressing neurons, which orchestrates the fine-tuning of DA regulation in the thalamo-cortico-striatal loops. One-Sentence Summary D1/D2 SPNs modulate the motor function of both D1- and D2-SPN