Dopamine-Orchestrated Synaptic Plasticity through Circuit- and Cell-Type-Specific Mechanisms in the Basal Ganglia

Abstract

The Basal Ganglia (BG) circuitry is the central hub for action selection, motor control, and reward- based learning. Dopamine (DA) is a key neuromodulator that flexibly regulates synaptic plasticity across BG circuits, enabling adaptive control of movement and learning. Although dopaminergic regulation has been extensively studied in the striatum, the precise mechanisms by which DA fine-tunes synaptic plasticity across distinct cellular and circuit domains remain largely unknown. Understanding this circuit- and cell-type-specific heterogeneity in DA signaling is essential for comprehending how BG output adapts to internal and external demands, and how its dysregulation contributes to movement disorders such as Parkinson’s disease (PD). In this dissertation, I investigate how DA orchestrates synaptic plasticity across multiple levels of the BG through distinct neuronal and astrocytic mechanisms. Specifically, I focused on two complementary pathways, the striatopallidal synapse in the external globus pallidus (GPe), which represents the first inhibitory relay of the indirect pathway, and the corticostriatal synapse, where DA and astrocytes cooperatively shape excitatory remodeling during motor learning. In Chapter 3, I demonstrate that DA modulates striatopallidal inhibitory transmission in a subregion- specific manner through distinct pre- and postsynaptic receptor mechanisms. I found that presynaptic D2 receptors and postsynaptic D4 receptors differentially shape short-term plasticity across GPe subregions exhibiting a pinwheel-like topographical organization. DA depletion reorganizes these regional patterns by altering D2R localization and calcium dynamics at striatopallidal terminals, revealing that dopaminergic signaling in the GPe is spatially heterogeneous yet functionally precise. In Chapter 4, I reveal that DA also governs long-term excitatory plasticity through astrocytic mechanisms. I find that DA-dependent astrocytic MEGF10 signaling drives synapse-specific engulfment of corticostriatal inputs during motor learning. Through ex vivo whole-cell recordings, I demonstrate that astrocytic MEGF10 is required for maintaining corticostriatal synaptic strength and quantal properties following motor learning. Using distinct paradigms of motor learning and chemogenetic DA modulation, I further reveal that astrocytic MEGF10 is required for learning-induced synaptic strengthening and DA-dependent regulation of corticostriatal transmission in D1- and D2- medium spiny neurons (MSNs). These electrophysiological findings establish the functional necessity of astrocyte-mediated synaptic remodeling for DA-driven circuit refinement and motor adaptation. In Chapter 5, I summarize the key findings of this dissertation and discuss their broader implications for BG function. Altogether, my research identifies DA as a key orchestrator of synaptic architecture— through highly structured regulation that coordinates fast, region-specific modulation of inhibitory transmission and slow, astrocyte-dependent remodeling of excitatory connections. This dual mechanism provides new insight into how DA confers both flexibility and stability to BG networks and suggests potential therapeutic targets for movement disorders associated with dopaminergic dysfunction.