Distinct modes of dopaminergic modulation on striatopallidal transmission in health and Parkinsonism

Abstract

Dopamine (DA) and its GPCR receptors control willed movement through the D1-direct pathway and D2-indirect pathway within the basal ganglia. In a classical model, excessive activity in the indirect pathway is one of the circuit mechanisms underlying parkinsonism. Although striatopallidal synapses serve as a critical gateway of the indirect pathway, the physiological functions of dopamine on striatopallidal transmission remain poorly understood. Here, we sought to understand how DA through the nigropallidal pathway modulates striatopallidal transmission. We found that DA is directly released onto the GPe and there is a marked regional heterogeneity of dopaminergic innervation to the GPe. In addition, striatopallidal transmission is physiologically different within the subregions of the GPe defined by the dorsal-ventral and lateral-medial axes. We further showed that dopamine D2-Like receptors modulate striatopallidal transmission via regionally distinct modes of action in the GPe. We also revealed that the differences in subcellular expression and sensitivity of dopamine D2 and D4 receptors expressed on striatopallidal terminals and postsynaptic GPe neurons are likely to make a contribution to the diversity of dopaminergic modulation on striatopallidal transmission throughout the GPe subregions. Notably, nigropallidal dopaminergic innervations to the GPe subregions exhibit differential susceptibility to 6-OHDA. Moreover, 6-OHDA-induced DA depletion particularly promotes D2R-mediated presynaptic inhibition in VL and DM subregions of the GPe. To sum up, these results demonstrate that synaptic information conveyed by the indirect pathway can be differentially regulated by DA via distinct modes of action in the GPe subregions, which can be determined by anatomical locations of striatopallidal synapses.