Distinct modes of dopaminergic modulation on striatopallidal synaptic transmission

Abstract

Dopamine is crucial in controlling voluntary movements through the D1 -direct and D2-indirect pathways in the basal ganglia, In a classical model , overactivity in the indirect pathway is one of the circuit mechanisms underlying parkinsonism . However, the role of dopamine on striatopallidal synapses, a key component of the indirect pathway, is not well understood due to limited dopaminergic innervation in the external globus pallidus (GPe) . Here, we seek to understand how DA through the nigropallidal pathway modulates striatopallidal transmission . Utilizing electrophys iology, optogenetics, GRAB sensor, pharmacology, enhanced confocal imaging , and synapse analysis, we discovered that dopamine is directly released onto the GPe, with notable regional differences in dopaminergic innervation . Additionally , dopamine D2-like receptors were found to modulate striatopallidal synaptic transmission in distinct ways. Notably, nigropallidal dopaminergic innervations to the GPe subregions exhibit differential susceptibility to 6-0HDA. Moreover, 6-0HDA- 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 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.