| الوصف: |
Mesostriatal dopamine (DA) signalling plays a central role in the functions of the basal ganglia, facilitating behavioural processes such as action selection and reinforcement learning. Consequently, dysregulation of DA signalling is implicated in a diversity of neurological and psychiatric disorders including Parkinson’s disease and addictions. It is increasingly appreciated that DA output from DA axons in striatum is subject to major influences besides action potentials generated at the level of the cell body. Rather, local mechanisms in the striatum are able to drive and gate axonal DA release. Unravelling these mechanisms and understanding how they might be dysfunctional in diseases with DA dysregulation, is critical for identifying novel targets for disease-modifying therapies. The striatum contains a high density of GABAergic projection neurons and interneurons, and in addition midbrain DA neurons also co-release GABA in striatum. Extrasynaptic striatal GABA can accumulate to exert tonic inhibition of principal striatal neurons as an ambient GABA tone, the level of which is determined by plasma membrane GABA uptake transporters (GATs). However, whether striatal GABA, and subsequently GATs, can modulate DA release are unknown. This thesis examines how striatal GABA signalling and GATs govern DA release in mouse striatum, and how they are dysfunctional in a mouse model of early Parkinsonism. The work presented in the first part of this thesis addressed whether striatal GABA and its receptors can directly modulate DA release using fast-scan cyclic voltammetry in mouse brain slices. DA release was found to be inhibited by the activation of GABAA and GABAB receptors. Furthermore, GABA receptor antagonists significantly enhanced DA release evoked by optogenetic stimulation, indicating that DA release is under tonic inhibition by striatal GABA. In testing whether striatal GATs determine DA output through limiting GABA tone onto DA axons, GAT-1 and GAT-3 are revealed to govern DA release in dorsolateral striatum, but not nucleus accumbens core, and exhibited correspondingly enriched expression in dorsolateral striatum. Further, GAT-3 and GAT-1 localised to striatal astrocytes were found to critically regulate the level of GABA inhibition of DA release, as astrocyte inactivation prevented the effects of GAT inhibition. The second part of this thesis examined whether this exposed GABAergic regulation of DA release is dysfunctional in a human α-synuclein overexpressing mouse model of early Parkinsonism. GAT function and expression were revealed to be downregulated and tonic GABAergic inhibition of DA release correspondingly augmented in the dorsolateral striatum, but not accumbens core, despite attenuated GABA co-release from dopaminergic axons. Additionally, a multiple dose course of the gabapentinoid pregabalin was found to boost DA release specifically in dorsolateral striatum, potentially mediated by normalising dysregulated tonic GABAergic inhibition of DA release in this mouse model of early Parkinsonism. These data define previously unappreciated and important roles for GABA, GATs and astrocytes in sculpting DA release in striatum, and reveal that they underlie maladaptive plasticity in early Parkinsonism that impairs DA output in vulnerable striatal regions. |
