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

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• 作者：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
• 关键词：Parkinson's disease ; 伪-Synuclein ; Dopamine ; Norepinephrine ; Voltammetry ; Behavior
• 刊名：Neurobiology of Disease
• 出版年：February, 2014
• 年：2014
• 卷：62
• 期：Complete
• 页码：193-207
• 全文大小：2424 K

文摘

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 伪-synuclein. Approximately 5-10% of PD patients have a familial form of Parkinsonism, including mutations in 伪-synuclein. To better understand the cell-type specific role of 伪-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 伪-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 鈭?鈭?/em>) background. The BAC transgenic mice expressed 伪-synuclein in tyrosine hydroxylase-positive neurons and expression of either A30P 伪-synuclein or wildtype 伪-synuclein restored the sensitivity of DA neurons to MPTP in resistant Snca 鈭?鈭?/em> animals. A30P 伪-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 鈭?鈭?/em> mice but no changes to release of another catecholamine, norepinephrine (NE), in the NE-rich ventral bed nucleus of stria terminalis. SNCA-A30P Snca 鈭?鈭?/em> mice had no overt behavioral impairments but exhibited a mild increase in wheel-running. In summary, this refined PD mouse model shows that A30P 伪-synuclein preferentially perturbs the dopaminergic system in the dorsal striatum, reflecting the region-specific change seen in PD.