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

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 a-synuclein. Approximately 5-10% of PD patients have a familial form of Parkinsonism, including mutations in a-synuclein. To better understand the cell-type specific role of a-synudein on DA neurotransmission, and the effects of the disease-associated A3OP mutation, we generated and studied a novel transgenic model of PD. We expressed the A3OP mutant form of human a-synudein 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 alpha-synuclein in tyrosine hydroxylase-positive neurons and expression of either A3OP alpha-synuclein or wildtype alpha-synuclein restored the sensitivity of DA neurons to MPTP in resistant Snca-/- animals. A3OP alpha-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-A3OP Snca-/- mice but no changes to release of another catecholamine, norepinephrine (NE), in the NE-rich ventral bed nucleus of stria terminalis. SNCA-A3OP Snca-/- mice had no overt behavioral impairments but exhibited a mild increase in wheel-running. In summary, this refined PD mouse model shows that MOP asynuclein preferentially perturbs the dopaminergic system in the dorsal striatum, reflecting the region-specific change seen in PD. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.