Astrocytic striatal GABA transporter activity governs dopamine release and shows maladaptive downregulation in early parkinsonism
| Autor: | Peter J. Magill, Natalie M. Doig, Katherine R. Brimblecombe, N Pasternack, Stephanie J. Cragg, Natalie Connor-Robson, Sarah Threlfell, Emanuel F. Lopes, Bradley M. Roberts, Ruth E. Siddorn, Nora Bengoa-Vergniory, Richard Wade-Martins |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
genetic structures Chemistry Parkinsonism Dopaminergic GABA transporter activity Striatum Nucleus accumbens medicine.disease Tonic (physiology) 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation nervous system Dopamine medicine Neuroscience 030217 neurology & neurosurgery 030304 developmental biology medicine.drug |
| DOI: | 10.1101/698274 |
| Popis: | SummaryStriatal dopamine (DA) is critical for action and learning. Recent data show DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be governed by plasma membrane GABA uptake transporters (GATs) on astrocytes. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs were downregulated and tonic GABAergic inhibition of DA release augmented, with corresponding attenuation of GABA co-release from dopaminergic axons. These data define previously unappreciated and important roles for GATs and astrocytes in determining DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions.HighlightsGABA transporters set the level of GABA inhibition of DA output in dorsal striatumAstrocytes facilitate DA release levels by limiting tonic GABA inhibitionTonic inhibition of DA release is augmented in a mouse model of early parkinsonismDA and GABA co-release are reduced in a mouse model of early parkinsonism |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|