Distinct modes of dopamine modulation on striatopallidal synaptic transmission

Abstract

Dopamine (DA) plays a crucial role in voluntary movement by modulating basal ganglia function. According to the classical model, DA depletion leads to overactivation of the indirect pathway, excessive thalamic inhibition, and ultimately hypokinesia. Although the striatopallidal synapse—linking the striatum to the external globus pallidus (GPe)—is a key node in this pathway, its dopaminergic modulation remains poorly understood due to sparse DA innervation. To address this, we combined projection-specific optogenetics, whole-cell patch-clamp recordings in acute mouse brain slices, and computational modeling. We found that DA exerts region-specific effects through D2 and D4 receptors in the GPe. In dorsolateral (DL) and ventromedial (VM) GPe, D2 receptors mediate presynaptic inhibition by increasing paired-pulse ratio (PPR) and reducing GABA release. In contrast, in dorsomedial (DM) and ventrolateral (VL) GPe, D4 receptors mediate postsynaptic inhibition without affecting PPR. This reveals a spatially organized, pinwheel-like pattern of DA signaling across GPe subregions. Following 6-hydroxydopamine (6-OHDA)-induced DA depletion, this spatial pattern reverses: PPR increases in the VL and DM while diminishing in the DL and VM. Together, our findings demonstrate that striatopallidal synapses are spatially organized and differentially modulated by dopamine across GPe subregions. This structured dopaminergic modulation enables selective gating of indirect pathway signals and may contribute to region-specific dysfunctions in Parkinsonian states. Understanding this spatial logic provides new insight into the functional architecture and pathological vulnerability of basal ganglia circuits.