Dopamine transporter and GABA receptor regulation of striatal dopamine release

Thesis

Mesostriatal dopamine (DA) neurons form extensive axonal arbours in the striatum, where DA signalling plays a key role in basal ganglia function and dysfunction. To understand striatal DA signalling, it is imperative to investigate the diverse, interacting mechanisms that govern DA release and uptake. DA transporters (DATs) have varied, complex roles, not only governing the extracellular lifetime of DA, but also shaping DA release probability and its short-term plasticity. The striatum is enriched in γ-aminobutyric acid (GABA)-containing neurons, where GABA mediates tonic inhibition of striatal DA release and also modestly regulates short-term plasticity. DATs and GABA receptors (GABA-Rs) appear to operate some parallel functions, limiting striatal DA release probability and axonal activation, yet supporting the frequency-dependence of DA release. I investigated whether DATs and GABA-Rs co-operate to determine striatal DA release. Work presented in this thesis used fast-scan cyclic voltammetry and imaging of genetically-encoded fluorescent voltage indicators in mouse striatum ex vivo to explore the convergent regulation of DA release by DATs and GABA-Rs, and to test directly whether DATs modulate axonal excitability.

In the dorsal striatum, I found that GABA-Rs support DAT-mediated changes to DA release, without affecting DA uptake, whereas in the ventral striatum, co-operation between DATs and GABA-Rs was not readily apparent. I subsequently explored the contribution of G protein-gated inwardly rectifying K⁺ (GIRK) channels to the control of DA release by DATs and GABA-Rs. Finally, I show that DAT-mediated currents modulate axonal membrane potential, in a manner consistent with governing short-term plasticity in DA release. These findings indicate that striatal DA axons integrate signalling from DATs and GABA-Rs to shape axonal excitability and DA output.

Authors: O'Connor, B

• DOI: 10.5287/ora-xmkbkqpqz
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: GABA; voltage indicator imaging; dopamine; fast scan cyclic voltammetry; striatum
• Subjects: Neurosciences