title: Region-specific deficits in dopamine, but not norepinephrine, signaling in a novel A30P α-synuclein BAC transgenic mouse.
abstract: 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 111kb 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.
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
authors.forename: Tonya N
authors.initials: TN
authors.lastname: Taylor
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
authors.forename: Dawid
authors.initials: D
authors.lastname: Potgieter
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
authors.forename: Sabina
authors.initials: S
authors.lastname: Anwar
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Senior
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Janezic
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Threlfell
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
authors.forename: Brent
authors.initials: B
authors.lastname: Ryan
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, University of Oxford, Oxford, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Parkkinen
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
authors.forename: Thierry
authors.initials: T
authors.lastname: Deltheil
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
authors.forename: Milena
authors.initials: M
authors.lastname: Cioroch
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK; MRC Functional Genomics Unit, University of Oxford, Oxford, UK.
authors.forename: Achilleas
authors.initials: A
authors.lastname: Livieratos
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK; MRC Functional Genomics Unit, University of Oxford, Oxford, UK.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Oliver
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
authors.forename: Katie A
authors.initials: KA
authors.lastname: Jennings
authors.affiliation: Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK; MRC Functional Genomics Unit, University of Oxford, Oxford, UK.
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Nuffield Department of Clinical Neuroscience, John Radcliffe Hospital, University of Oxford, Oxford, UK.
authors.forename: Olaf
authors.initials: O
authors.lastname: Ansorge
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Experimental Psychology, University of Oxford, Oxford, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Bannerman
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Cragg
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK. Electronic address: richard.wade-martins@dpag.ox.ac.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Wade-Martins
mesh_terms: D000367:Age Factors; D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism*; D022202:Chromosomes, Artificial, Bacterial; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009638:Norepinephrine / Q000378:metabolism*; D012686:Septal Nuclei / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein; D004298:Dopamine; D009638:Norepinephrine
keywords: Behavior; Dopamine; Norepinephrine; Parkinson's disease; Voltammetry; α-Synuclein