Distinct modes of dopaminergic modulation on striatopallidal synaptic transmission

Abstract

The basal ganglia, a network of subcortical structures are the core brain regions of initiating voluntary movement. To regulate the basal ganglia function properly, the modulatory neurotransmitter dopamine (DA) is essential. The striatopallidal synapse, as the first gateway of the indirect pathway, is a critical point where widely distributed iMSN axon terminals converge. Studies to date have found little evidence that DA is directly released onto the GPe, modulating striatopallidal synaptic transmission. Furthermore, it has been appreciated that there is anatomically dichotomous dopaminergic innervation throughout the striatum and each subdivision of the striatum is involved with different behaviors. In this process, it remains uncertain whether dopamine innervates GPe in anatomically heterogeneous patterns and leads to different patterns of modulation. Here, we examined the role of dopamine in modulating the striatopallidal synaptic transmission in the view of ‘innervation’, ‘modulation’, and ‘denervation’. Our data therefore demonstrate that functional dopamine boutons innervate the GPe with regional heterogeneity and DA modulates striatopallidal transmission with notable regional heterogeneity via presynaptic D2 dopamine receptors (D2R) and postsynaptic D4 dopamine receptors (D4R), shaping various ongoing activity outputs. Notably, 6-OHDA-induced DA depletion reversed the region- specific dopaminergic modulation in a way of maintaining homeostasis, with differential susceptibility to 6-OHDA. Thus, DA heterogeneously innervates the GPe, thereby modulating synaptic information conveyed by the indirect pathway via distinct modes. Since the 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.