Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human α-synuclein.

Hatos Center, University of California Los Angeles, Los Angeles, California, USA.
Journal of Neuroscience Research (Impact Factor: 2.73). 07/2011; 89(7):1091-102. DOI: 10.1002/jnr.22611
Source: PubMed

ABSTRACT Overexpression or mutation of α-synuclein (α-Syn), a protein associated with presynaptic vesicles, causes familial forms of Parkinson's disease in humans and is also associated with sporadic forms of the disease. We used in vivo microdialysis, tissue content analysis, behavioral assessment, and whole-cell patch clamp recordings from striatal medium-sized spiny neurons (MSSNs) in slices to examine dopamine transmission and dopaminergic modulation of corticostriatal synaptic function in mice overexpressing human wild-type α-Syn under the Thy1 promoter (α-Syn mice). Tonic striatal extracellular dopamine and 3-methoxytyramine levels were elevated in α-Syn mice at 6 months of age, prior to any reduction in total striatal tissue content, and were accompanied by an increase in open-field activity. Dopamine clearance and amphetamine-induced dopamine efflux were unchanged. The frequency of MSSN spontaneous excitatory postsynaptic currents (sEPSCs) was lower in α-Syn mice. Amphetamine reduced sEPSC frequency in wild types (WTs) but produced no effect in α-Syn mice. Furthermore, whereas quinpirole reduced and sulpiride increased sEPSC frequency in WT mice, they produced the opposite effects in α-Syn mice. These observations indicate that overexpression of α-Syn alters dopamine efflux and D2 receptor modulation of corticostriatal glutamate release at a young age. At 14 months of age, the α-Syn mice presented with significantly lower striatal tissue dopamine and tyrosine hydroxylase content relative to WT littermates, accompanied by an L-DOPA-reversible sensory motor deficit. Together, these data further validate this transgenic mouse line as a slowly progressing model of Parkinson's disease and provide evidence for early dopamine synaptic dysfunction prior to loss of striatal dopamine.

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    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder that affects about 1.5% of the global population over 65 years of age. A hallmark feature of PD is the degeneration of the dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and the consequent striatal DA deficiency. Yet, the pathogenesis of PD remains unclear. Despite tremendous growth in recent years in our knowledge of the molecular basis of PD and the molecular pathways of cell death, important questions remain, such as: 1) why are SNc cells especially vulnerable; 2) which mechanisms underlie progressive SNc cell loss; and 3) what do Lewy bodies or α-synuclein reveal about disease progression. Understanding the variable vulnerability of the dopaminergic neurons from the midbrain and the mechanisms whereby pathology becomes widespread are some of the primary objectives of research in PD. Animal models are the best tools to study the pathogenesis of PD. The identification of PD-related genes has led to the development of genetic PD models as an alternative to the classical toxin-based ones, but does the dopaminergic neuronal loss in actual animal models adequately recapitulate that of the human disease? The selection of a particular animal model is very important for the specific goals of the different experiments. In this review, we provide a summary of our current knowledge about the different in vivo models of PD that are used in relation to the vulnerability of the dopaminergic neurons in the midbrain in the pathogenesis of PD.
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    ABSTRACT: A preferential dysfunction/loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) accounts for the main motor symptoms of Parkinson's disease (PD), the most common degenerative movement disorder. However, the neuronal loss is not stochastic, but rather displays regionally selectivity, indicating the existence of different DA subpopulations in the SNpc. To identify the underlying molecular determinants is thereby instrumental in understanding the pathophysiological mechanisms of PD-related neuron dysfunction/loss and offering new therapeutic targets. Recently, we have demonstrated that aldehyde dehydrogenase 1 (ALDH1A1) is one such molecular determinant that defines and protects an SNpc DA neuron subpopulation preferentially affected in PD. In this review, we provide further analysis and discussion on the roles of ALDH1A1 in the function and survival of SNpc DA neurons in both rodent and human brains. We also explore the feasibility of ALDH1A1 as a potential biomarker and therapeutic target for PD.
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    ABSTRACT: α-Synuclein is thought to regulate neurotransmitter release through multiple interactions with presynaptic proteins, cytoskeletal elements, ion channels, and synaptic vesicles membrane. α-Synuclein is abundant in the presynaptic compartment, and its release from neurons and glia has been described as responsible for spreading of α-synuclein-derived pathology. α-Synuclein-dependent dysregulation of neurotransmitter release might occur via its action on surface-exposed calcium channels. Here, we provide electrophysiological and biochemical evidence to show that α-synuclein, applied to rat neurons in culture or striatal slices, selectively activates Cav2.2 channels, and said activation correlates with increased neurotransmitter release. Furthermore, in vivo perfusion of α-synuclein into the striatum also leads to acute dopamine release. We further demonstrate that α-synuclein reduces the amount of plasma membrane cholesterol and alters the partitioning of Cav2.2 channels, which move from raft to cholesterol-poor areas of the plasma membrane. We provide evidence for a novel mechanism through which α-synuclein acts from the extracellular milieu to modulate neurotransmitter release and propose a unifying hypothesis for the mechanism of α-synuclein action on multiple targets: the reorganization of plasma membrane microdomains.
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Aug 4, 2014