Distinct modes of dopamine modulation on striatopallidal synaptic transmission

Dopamine affects voluntary movement by modulating basal ganglia function. However, the contribution of dopamine on striatopallidal synapses, an initial hub in the indirect pathway connecting the striatum to the GPe, remains poorly understood because of the sparse dopaminergic innervation. Here, we combine optogenetic projection targeting, whole cell patch clamp recordings in acute brain slices from mice, and computational modeling to overcome this limitation. We show that dopamine activates D2 receptors (D2Rs) and D4 receptors (D4Rs) differentially in distinct GPe subregions. In a pinwheel-like fashion, dorsolateral and ventromedial GPe expresses high levels of D2Rs, which exert presynaptic inhibition, while in dorsomedial and ventrolateral GPe D4Rs cause postsynaptic inhibition. Dopamine depletion by 6-OHDA reshapes the region-specific effect of dopamine, shifting it in the opposite direction and contributing to hypokinesia. These findings reveal the mechanism by which the different modality information conveyed spatially through the indirect pathway is differentially modulated by dopamine at striatopallidal synapses. Whether dopaminergic modulation of synaptic transmission can vary by the anatomical location of striatopallidal synapses in the GPe (external globus pallidus) is not fully understood. Here authors demonstrate that dopamine fine-tunes striatopallidal synaptic transmission by acting on presynaptic D2 and postsynaptic D4 receptors across subregions of the GPe. In addition, dopamine depletion reshapes this modulation in the opposite direction.