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Region-specific deficits in dopamine, but not norepinephrine, signaling in a novel A30P ?-synuclein BAC transgenic mouse.
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Neurobiol Dis 2013 Oct;
Authors: 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
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
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 ?-synuclein. Approximately 5-10% of PD patients have a familial form of Parkinsonism, including mutations in ?-synuclein. To better understand the cell-type specific role of ?-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 ?-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 ?-synuclein in tyrosine hydroxylase-positive neurons and expression of either A30P ?-synuclein or wildtype ?-synuclein restored the sensitivity of DA neurons to MPTP in resistant Snca-/- animals. A30P ?-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 ?-synuclein preferentially perturbs the dopaminergic system in the dorsal striatum, reflecting the region-specific change seen in PD.
PMID: 24121116 [PubMed - as supplied by publisher]