Abstract

Dopamine affects voluntary movement by modulating basal ganglia function. However, the contribution of dopamine on striatopallidal synapses, an initial hub in the indirect pathway connecting the striatum to the GPe, remains poorly understood because of the sparse dopaminergic innervation. Here, we combine optogenetic projection targeting, whole cell patch clamp recordings in acute brain slices from mice, and computational modeling to overcome this limitation. We show that dopamine activates D2 receptors (D2Rs) and D4 receptors (D4Rs) differentially in distinct GPe subregions. In a pinwheel-like fashion, dorsolateral and ventromedial GPe expresses high levels of D2Rs, which exert presynaptic inhibition, while in dorsomedial and ventrolateral GPe D4Rs cause postsynaptic inhibition. Dopamine depletion by 6-OHDA reshapes the region-specific effect of dopamine, shifting it in the opposite direction and contributing to hypokinesia. These findings reveal the mechanism by which the different modality information conveyed spatially through the indirect pathway is differentially modulated by dopamine at striatopallidal synapses.

Researchers at UNIST have identified a novel spatial rule, governing how dopamine modulates inhibitory signals in the brain’s basal ganglia, deepening our understanding of motor control and opening new avenues for targeted therapies in neurodegenerative diseases, such as Parkinson’s. 

The study, led by Professor Jae-Ick Kim of the Department of Biological Sciences, reveals that dopamine’s influence on synapses within the indirect pathway of the basal ganglia varies depending on the specific subregion. Using advanced techniques—including optogenetics, electrophysiology, and computational modeling—the team demonstrated that dopamine differentially regulates GABAergic inhibitory signals through distinct receptor types in different parts of the external globus pallidus (GPe). 

Specifically, dopamine reduces inhibitory GABA release via D2 receptors in the dorsolateral and ventromedial GPe regions, weakening inhibition. Conversely, in the dorsomedial and ventrolateral regions, dopamine acts through D4 receptors to suppress postsynaptic activity, also diminishing overall inhibition. This regional specificity suggests that dopamine fine-tunes motor signals in a highly localized manner. 

Remarkably, in a Parkinson’s model characterized by dopamine depletion, these region-specific modulation patterns are reversed, indicating that the spatial regulation of dopamine is critical for normal motor function. Such insights could inform the development of more precise interventions targeting specific brain regions and receptor subtypes. 

Professor Lee commented on the findings, "Understanding how dopamine differently modulates circuits based on region and receptor type provides a foundation for developing targeted therapies for movement disorders."

Youngeun Lee, the lead researcher, added, "Our study highlights the importance of regional and receptor-specific modulation within the brain's motor circuits, which could lead to more effective treatment strategies."

Published in Nature Communications on April 3, this research offers vital neurophysiological insights for designing treatments for movement disorders. This study has been supported by the Mid-Career Researcher Program and the Bio & Medical Technology Development Program of the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (MSIT). 

Journal Reference

Youngeun Lina Lee, Maria Reva, Ki Jung Kim, et al ., “Distinct modes of dopamine modulation on striatopallidal synaptic transmission,” Nat. Commun ., (2026).