Region-specific deficits in dopamine, but not norepinephrine, signaling in a novel A30P α-synuclein BAC transgenic mouse

Tonya N. Taylor; Dawid Potgieter; Sabina Anwar; Steven L. Senior; Stephanie Janezic; Sarah Threlfell; Brent Ryan; Laura Parkkinen; Thierry Deltheil; Milena Cioroch; Achilleas Livieratos; Peter L. Oliver; Katie A. Jennings; Kay E. Davies; Olaf Ansorge; David M. Bannerman; Stephanie J. Cragg; Richard Wade-Martins

Neurobiology of Disease (Feb 2014)

Region-specific deficits in dopamine, but not norepinephrine, signaling in a novel A30P α-synuclein BAC transgenic mouse

Tonya N. Taylor,
Dawid Potgieter,
Sabina Anwar,
Steven L. Senior,
Stephanie Janezic,
Sarah Threlfell,
Brent Ryan,
Laura Parkkinen,
Thierry Deltheil,
Milena Cioroch,
Achilleas Livieratos,
Peter L. Oliver,
Katie A. Jennings,
Kay E. Davies,
Olaf Ansorge,
David M. Bannerman,
Stephanie J. Cragg,
Richard Wade-Martins

Affiliations

Tonya N. Taylor: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
Dawid Potgieter: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
Sabina Anwar: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
Steven L. Senior: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
Stephanie Janezic: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
Sarah Threlfell: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
Brent Ryan: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
Laura Parkkinen: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, University of Oxford, Oxford, UK
Thierry Deltheil: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
Milena Cioroch: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
Achilleas Livieratos: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK; MRC Functional Genomics Unit, University of Oxford, Oxford, UK
Peter L. Oliver: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK; MRC Functional Genomics Unit, University of Oxford, Oxford, UK
Katie A. Jennings: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
Kay E. Davies: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK; MRC Functional Genomics Unit, University of Oxford, Oxford, UK
Olaf Ansorge: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, University of Oxford, Oxford, UK
David M. Bannerman: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Experimental Psychology, University of Oxford, Oxford, UK
Stephanie J. Cragg: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
Richard Wade-Martins: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK; Corresponding author at: Department of Physiology, Anatomy, and Genetics, Le Gros Clark Building, South Parks Road, University of Oxford, Oxford OX1 3QX, UK.

Journal volume & issue: Vol. 62
pp. 193 – 207

Abstract

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Parkinson's disease (PD) is a neurodegenerative disorder classically characterized by the death of dopamine (DA) neurons in the substantia nigra pars compacta and by intracellular Lewy bodies composed largely of α-synuclein. Approximately 5–10% of PD patients have a familial form of Parkinsonism, including mutations in α-synuclein. To better understand the cell-type specific role of α-synuclein on DA neurotransmission, and the effects of the disease-associated A30P mutation, we generated and studied a novel transgenic model of PD. We expressed the A30P mutant form of human α-synuclein in a spatially-relevant manner from the 111 kb SNCA genomic DNA locus on a bacterial artificial chromosome (BAC) insert on a mouse null (Snca−/−) background. The BAC transgenic mice expressed α-synuclein in tyrosine hydroxylase-positive neurons and expression of either A30P α-synuclein or wildtype α-synuclein restored the sensitivity of DA neurons to MPTP in resistant Snca−/− animals. A30P α-synuclein mice showed no Lewy body-like aggregation, and did not lose catecholamine neurons in substantia nigra or locus coeruleus. However, using cyclic voltammetry at carbon-fiber microelectrodes we identified a deficit in evoked DA release in the caudate putamen, but not in the nucleus accumbens, of SNCA-A30P Snca−/− mice but no changes to release of another catecholamine, norepinephrine (NE), in the NE-rich ventral bed nucleus of stria terminalis. SNCA-A30P Snca−/− mice had no overt behavioral impairments but exhibited a mild increase in wheel-running. In summary, this refined PD mouse model shows that A30P α-synuclein preferentially perturbs the dopaminergic system in the dorsal striatum, reflecting the region-specific change seen in PD.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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