Movement disorders : official journal of the Movement Disorder Society · 2017
Striatal D1 medium spiny neuron activation induces dyskinesias in parkinsonian mice.
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Perez Xiomara A, Zhang Danhui, Bordia Tanuja, Quik Maryka
Аннотация
BACKGROUND: Dyskinesias are a disabling motor complication that arises with prolonged l-dopa treatment. Studies using D1 receptor drugs and genetically modified mice suggest that medium spiny neurons expressing D1 receptors play a primary role in l-dopa-induced dyskinesias. However, the specific role of these neurons in dyskinesias is not fully understood.
METHODS: We used optogenetics, which allows for precise modulation of select neurons in vivo, to investigate whether striatal D1-expressing medium spiny neuron activity regulates abnormal involuntary movements or dyskinesia in parkinsonian mice. D1-cre mice unilaterally lesioned with 6-hydroxydopamine received striatal injections of cre-dependent channelrhodopsin2 virus or control virus. After stable virus expression, the effect of optical stimulation on dyskinesia was tested in l-dopa-naïve and l-dopa-primed mice.
RESULTS: Single-pulse and burst-optical stimulation of D1-expressing medium spiny neurons induced dyskinesias in l-dopa-naïve channelrhodopsin2 mice. In stably dyskinetic mice, l-dopa injection induced dyskinesia to a similar or somewhat greater extent than optical stimulation. Combined l-dopa administration and stimulation resulted in an additive increase in dyskinesias, indicating that other mechanisms also contribute. Molecular studies indicate that changes in extracellular signal-regulated kinase phosphorylation in D1-expressing medium spiny neurons are involved. Optical stimulation did not ameliorate parkinsonism in l-dopa-naïve mice. However, it improved parkinsonism in l-dopa-primed mice to a similar extent as l-dopa administration. None of the stimulation paradigms enhanced dyskinesia or modified parkinsonism in l-dopa-naïve or l-dopa-primed control virus mice.
CONCLUSION: The data provide direct evidence that striatal D1-expressing medium spiny neuron stimulation is sufficient to induce dyskinesias and contributes to the regulation of motor control. © 2017 International Parkinson and Movement Disorder Society.
METHODS: We used optogenetics, which allows for precise modulation of select neurons in vivo, to investigate whether striatal D1-expressing medium spiny neuron activity regulates abnormal involuntary movements or dyskinesia in parkinsonian mice. D1-cre mice unilaterally lesioned with 6-hydroxydopamine received striatal injections of cre-dependent channelrhodopsin2 virus or control virus. After stable virus expression, the effect of optical stimulation on dyskinesia was tested in l-dopa-naïve and l-dopa-primed mice.
RESULTS: Single-pulse and burst-optical stimulation of D1-expressing medium spiny neurons induced dyskinesias in l-dopa-naïve channelrhodopsin2 mice. In stably dyskinetic mice, l-dopa injection induced dyskinesia to a similar or somewhat greater extent than optical stimulation. Combined l-dopa administration and stimulation resulted in an additive increase in dyskinesias, indicating that other mechanisms also contribute. Molecular studies indicate that changes in extracellular signal-regulated kinase phosphorylation in D1-expressing medium spiny neurons are involved. Optical stimulation did not ameliorate parkinsonism in l-dopa-naïve mice. However, it improved parkinsonism in l-dopa-primed mice to a similar extent as l-dopa administration. None of the stimulation paradigms enhanced dyskinesia or modified parkinsonism in l-dopa-naïve or l-dopa-primed control virus mice.
CONCLUSION: The data provide direct evidence that striatal D1-expressing medium spiny neuron stimulation is sufficient to induce dyskinesias and contributes to the regulation of motor control. © 2017 International Parkinson and Movement Disorder Society.
Предметные рубрики MeSH
AnimalsAntiparkinson AgentsChannelrhodopsinsCocaineCorpus StriatumDisease Models, AnimalDopamine Plasma Membrane Transport ProteinsDyskinesiasFemaleGene Expression RegulationLevodopaMaleMiceMice, Inbred C57BLMice, TransgenicNeuronsOxidopamineParkinsonian DisordersReceptors, Dopamine D1Sympatholytics