alpha-synuclein and vanoxerine

Nigro-striatal dopamine transmission is central to a wide range of neuronal functions, including skill learning, which is disrupted in several pathologies such as Parkinson's disease. The synaptic plasticity mechanisms, by which initial motor learning is stored for long time periods in striatal neurons, to then be gradually optimized upon subsequent training, remain unexplored. Addressing this issue is crucial to identify the synaptic and molecular mechanisms involved in striatal-dependent learning impairment in Parkinson's disease. In this study, we took advantage of interindividual differences between outbred rodents in reaching plateau performance in the rotarod incremental motor learning protocol, to study striatal synaptic plasticity ex vivo. We then assessed how this process is modulated by dopamine receptors and the dopamine active transporter, and whether it is impaired by overexpression of human α-synuclein in the mesencephalon; the latter is a progressive animal model of Parkinson's disease. We found that the initial acquisition of motor learning induced a dopamine active transporter and D1 receptors mediated long-term potentiation, under a protocol of long-term depression in striatal medium spiny neurons. This effect disappeared in animals reaching performance plateau. Overexpression of human α-synuclein reduced striatal dopamine active transporter levels, impaired motor learning, and prevented the learning-induced long-term potentiation, before the appearance of dopamine neuronal loss. Our findings provide evidence of a reorganization of cellular plasticity within the dorsolateral striatum that is mediated by dopamine receptors and dopamine active transporter during the acquisition of a skill. This newly identified mechanism of cellular memory is a form of metaplasticity that is disrupted in the early stage of synucleinopathies, such as Parkinson's disease, and that might be relevant for other striatal pathologies, such as drug abuse.

Topics: alpha-Synuclein; Animals; Benzazepines; Corpus Striatum; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Green Fluorescent Proteins; Learning; Long-Term Potentiation; Male; Mice; Mice, Inbred C57BL; Motor Activity; Motor Skills; Neuronal Plasticity; Neurons; Piperazines; Reaction Time; Synapsins; Synaptophysin; Tyrosine 3-Monooxygenase

Mice lacking the pre-synaptic protein alpha-synuclein (α-syn) demonstrate enhanced facilitation of dopamine (DA) overflow in dorsal striatum following repeated, high-frequency burst stimulation of the dopaminergic pathways. Dorsal striatum is most vulnerable to neurodegeneration in Parkinson's disease. The role of α-syn in facilitation of DA overflow in the ventral striatum, which is less vulnerable to neurodegeneration, is unknown. We investigated the link between the absence of α-syn and the plasticity of DA overflow in the dorsal and ventral striatum by in vivo voltammetry and the possible mechanisms of modulation of the plasticity of DA overflow. We show that the facilitation of DA overflow following paired-burst stimulation is significantly enhanced in the dorsolateral but not in the ventral striatum of mice lacking α-syn. Re-uptake inhibitor, GBR12909, completely eliminated the facilitation of DA overflow regardless of the presence of α-syn in both dorsal and ventral striatum, indicating that re-uptake is critical for maintenance of paired-burst facilitation (PBF). Inhibition of D2 autoreceptors by haloperidol decreased PBF only in mice lacking α-syn. However, the basal function of D2 autoreceptors tested by paired-pulse depression of DA overflow was not different between the lines. Therefore, alterations in the D2 autoreceptor system do not explain the different effect of haloperidol on PBF in mice with and without α-syn. This indicates that neither re-uptake nor D2 autoreceptors differentiate the PBF between the genotypes. We propose that modification of DA vesicles in α-syn knockout mice, as reported in several studies, may be a factor underlying the enhanced PBF in these mice.

Topics: alpha-Synuclein; Analysis of Variance; Animals; Biophysical Phenomena; Biophysics; Blood Proteins; Brain Mapping; Corpus Striatum; Dopamine; Dopamine Antagonists; Dopamine Uptake Inhibitors; Electric Stimulation; Haloperidol; Male; Medial Forebrain Bundle; Mice; Mice, Inbred C57BL; Mice, Knockout; Neural Inhibition; Neuronal Plasticity; Piperazines; Time Factors

In humans, mutations in the alpha-synuclein gene or exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produce Parkinson's disease with loss of dopaminergic neurons and depletion of nigrostriatal dopamine. alpha-Synuclein is a vertebrate-specific component of presynaptic nerve terminals that may function in modulating synaptic transmission. To test whether MPTP toxicity involves alpha-synuclein, we generated alpha-synuclein-deficient mice by homologous recombination, and analyzed the effect of deleting alpha-synuclein on MPTP toxicity using these knockout mice. In addition, we examined commercially available mice that contain a spontaneous loss of the alpha-synuclein gene. As described previously, deletion of alpha-synuclein had no significant effects on brain structure or composition. In particular, the levels of synaptic proteins were not altered, and the concentrations of dopamine, dopamine metabolites, and dopaminergic proteins were unchanged. Upon acute MPTP challenge, alpha-synuclein knockout mice were partly protected from chronic depletion of nigrostriatal dopamine when compared with littermates of the same genetic background, whereas mice carrying the spontaneous deletion of the alpha-synuclein gene exhibited no protection. Furthermore, alpha-synuclein knockout mice but not the mice with the alpha-synuclein gene deletion were slightly more sensitive to methamphetamine than littermate control mice. These results demonstrate that alpha-synuclein is not obligatorily coupled to MPTP sensitivity, but can influence MPTP toxicity on some genetic backgrounds, and illustrate the need for extensive controls in studies aimed at describing the effects of mouse knockouts on MPTP sensitivity.

Topics: 3,4-Dihydroxyphenylacetic Acid; Adrenergic Uptake Inhibitors; alpha-Synuclein; Animals; Antibodies; Blastomeres; Blotting, Southern; Corpus Striatum; Disease Models, Animal; DNA Primers; Dopamine; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Glutamic Acid; Hippocampus; Homovanillic Acid; Humans; Immunoblotting; Immunohistochemistry; Methamphetamine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; MPTP Poisoning; Nerve Tissue Proteins; Neurons; Parkinsonian Disorders; Piperazines; Rats; Reserpine; Serotonin; Stem Cells; Subcellular Fractions; Substantia Nigra; Synucleins; Tyrosine 3-Monooxygenase