The pathological end-state of Parkinson disease is well described from postmortem tissue, but there remains a pressing need to define early functional changes to susceptible neurons and circuits. In particular, mechanisms underlying the vulnerability of the dopamine neurons of the substantia nigra pars compacta (SNc) and the importance of protein aggregation in driving the disease process remain to be determined. To better understand the sequence of events occurring in familial and sporadic Parkinson disease, we generated bacterial artificial chromosome transgenic mice (SNCA-OVX) that express wild-type α-synuclein from the complete human SNCA locus at disease-relevant levels and display a transgene expression profile that recapitulates that of endogenous α-synuclein. SNCA-OVX mice display age-dependent loss of nigrostriatal dopamine neurons and motor impairments characteristic of Parkinson disease. This phenotype is preceded by early deficits in dopamine release from terminals in the dorsal, but not ventral, striatum. Such neurotransmission deficits are not seen at either noradrenergic or serotoninergic terminals. Dopamine release deficits are associated with an altered distribution of vesicles in dopaminergic axons in the dorsal striatum. Aged SNCA-OVX mice exhibit reduced firing of SNc dopamine neurons in vivo measured by juxtacellular recording of neurochemically identified neurons. These progressive changes in vulnerable SNc neurons were observed independently of overt protein aggregation, suggesting neurophysiological changes precede, and are not driven by, aggregate formation. This longitudinal phenotyping strategy in SNCA-OVX mice thus provides insights into the region-specific neuronal disturbances preceding and accompanying Parkinson disease.dopamine transmission | in vivo electrophysiology | voltammetry | neurodegeneration | behavioral phenotyping T he development of new disease-modifying therapies for Parkinson disease (PD) is critically dependent on animal models that accurately recapitulate pathophysiological sequelae in an age-dependent manner. The generation of such models using genetically altered animals has proved challenging. The traditional use of heterologous gene promoters in the generation of transgenic mouse models precluded an endogenous transgene expression profile and produced additional phenotypes that are not characteristic of PD (1). In contrast, bacterial artificial chromosome (BAC) technology can enable expression of a desired transgene under the control of its native promoter and regulatory elements to achieve a correct spatiotemporal expression profile, thereby providing a more physiological model for investigating molecular mechanisms of the disease.The α-synuclein gene (SNCA) has been implicated in PD through three dominant point mutations (2-4) and locus multiplication (5, 6). SNCA duplications and triplications cause autosomal-dominant PD in which the age of onset and disease severity are related in a gene dosage-dependent manner (5, 6). More recently, genome-wide associatio...
Suppose that the state of a system of N n-level atoms is given by a tensor product of N identical density matrices. The exact formulas are presented that describe the probability that such a system may be found in a pure state with a given symmetry with respect to permutations of atoms. The asymptotic form of these probabilities valid for large N is also derived.
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