Two distinct modes of dopaminergic modulation on striatopallidal synaptic transmission

Abstract

Dopamine (DA) and its GPCR receptor control willed movement through D1-direct pathway and D2-indirect pathway within basal ganglia. In a classical model, excessive activity in indirect pathway is one of the circuit mechanisms underlying parkinsonism. Although striatopallidal synapses function as a critical gateway of indirect pathway, the physiological functions of dopamine on striatopallidal synapses remain unclear due to relatively sparse dopaminergic innervation on the external globus pallidus (GPe). Here, we seek to understand how DA through nigropallidal pathway modulates striatopallidal synaptic transmission. Utilizing electrophysiology, optogenetics, GRAB sensor, pharmacology, enhanced confocal imaging, and synapse analysis, we first revealed that DA is directly released onto the GPe and there is a marked regional heterogeneity of dopaminergic innervation to the GPe. In addition, we found that dopamine D2-like receptors modulate striatopallidal synaptic transmission via two distinct modes. The treatment of D2-like receptor agonist elevated paired-pulse ratio (PPR) and reduced GABAergic transmission at striatopallidal synapses located in dorsolateral (DL) and ventromedial (VM) GPe. Unexpectedly, however, PPR was not altered by the D2-like receptor agonist at striatopallidal synapses in ventrolateral (VL) and dorsomedial (DM) GPe, even with reduced GABAergic transmission. As potential mechanisms behind these distinct modes of dopaminergic modulation, we further found that D2 and D4 receptors in GPe subregions differentially regulate striatopallidal synaptic transmission through their differences in subcellular expression and sensitivity. In a DA-depleted animal model, nigropallidal dopaminergic fibers innervating each GPe subregion exhibited different susceptibility to 6-OHDA. Furthermore, DA depletion promoted presynaptic D2R-mediated inhibition at striatopallidal synapses in VL and DM subregions of the GPe potentially as a compensatory mechanism of DA loss. To sum up, these results demonstrate that synaptic information conveyed by indirect pathway can be regulated by DA via two distinct modes, which seem to be determined by anatomical locations of striatopallidal synapses in the GPe. Since structural and functional organization of basal ganglia circuits is critical to understanding both DA-related behaviors and DA-depleted pathological conditions such as Parkinson’s disease, our findings will provide new insights into the overlooked role of dopaminergic modulation on striatopallidal synapses and globus pallidus.