GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model.

Autor:	Roberts BM; Centre for Integrative Neuroscience, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK. bradley.roberts@dpag.ox.ac.uk.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, OX1 3PT, UK. bradley.roberts@dpag.ox.ac.uk., Doig NM; Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX1 3TH, UK., Brimblecombe KR; Centre for Integrative Neuroscience, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, OX1 3PT, UK., Lopes EF; Centre for Integrative Neuroscience, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK., Siddorn RE; Centre for Integrative Neuroscience, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK., Threlfell S; Centre for Integrative Neuroscience, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, OX1 3PT, UK., Connor-Robson N; Centre for Integrative Neuroscience, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, OX1 3PT, UK., Bengoa-Vergniory N; Centre for Integrative Neuroscience, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, OX1 3PT, UK., Pasternack N; Centre for Integrative Neuroscience, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK., Wade-Martins R; Centre for Integrative Neuroscience, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, OX1 3PT, UK., Magill PJ; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, OX1 3PT, UK.; Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX1 3TH, UK., Cragg SJ; Centre for Integrative Neuroscience, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK. stephanie.cragg@dpag.ox.ac.uk.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, OX1 3PT, UK. stephanie.cragg@dpag.ox.ac.uk.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 Oct 02; Vol. 11 (1), pp. 4958. Date of Electronic Publication: 2020 Oct 02.
DOI:	10.1038/s41467-020-18247-5
Abstrakt:	Striatal dopamine (DA) is critical for action and learning. Recent data show that DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be determined by plasma membrane GABA uptake transporters (GATs) located on astrocytes and neurons. 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 are downregulated, tonic GABAergic inhibition of DA release augmented, and nigrostriatal GABA co-release attenuated. These data define previously unappreciated and important roles for GATs and astrocytes in supporting DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions.
Databáze:	MEDLINE
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