Abstract
BackgroundThe pathophysiology of levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD) is not well understood. Experimental data from numerous investigations support the idea that aberrant activity of D1 dopamine receptor-positive medium spiny neurons in the striatal direct pathway is associated with LID. However, a direct link between the real-time activity of these striatal neurons and dyskinetic symptoms remains to be established.MethodsWe examined the effect of acute levodopa treatment on striatal c-Fos expression in LID using D1-Cre PD rats with dyskinetic symptoms induced by chronic levodopa administration. We studied the real-time dynamics of striatal D1+ neurons during dyskinetic behavior using GCaMP6-based in vivo fiber photometry. We also examined the effects of striatal D1+ neuronal deactivation on dyskinesia in LID rats using optogenetics and chemogenetic methods.ResultsStriatal D1+ neurons in LID rats showed increased expression of c-Fos, a widely used marker for neuronal activation, following levodopa injection. Fiber photometry revealed synchronized overactivity of striatal D1+ neurons during dyskinetic behavior in LID rats following levodopa administration. Consistent with these observations, optogenetic deactivation of striatal D1+ neurons was sufficient to inhibit most of the dyskinetic behaviors of LID animals. Moreover, chemogenetic inhibition of striatal D1+ neurons delayed the onset of dyskinetic behavior after levodopa administration.ConclusionOur data demonstrated that aberrant activity of striatal D1+ neuronal population was causally linked with real-time dyskinetic symptoms in LID rats.
Highlights
MATERIALS AND METHODSParkinson’s disease (PD) is a progressive neurodegenerative disorder that causes progressive motor deficits
We found that the activity of striatal D1+ neuronal population was causally linked with dyskinetic symptoms
Following unilateral 6-OHDA lesion of the MFB and chronic levodopa (6 mg/kg) treatment (Figure 1A), we evaluated the effect of striatal dopaminergic denervation on total Abnormal Involuntary Movement scale (AIMs) scores and striatal c-Fos expression at 80–100 min after subcutaneous injection of levodopa
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that causes progressive motor deficits. The dopamine precursor molecule, is the mainstay of symptomatic treatment for PD (Pezzoli and Zini, 2010). The positive effects of levodopa in PD often lead to the development of adverse motor fluctuations. Levodopa-induced dyskinesia (LID) is the most debilitating motor fluctuation after chronic administration of levodopa (Nadjar et al, 2009; Calabresi et al, 2010). The pathophysiology of levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD) is not well understood. Experimental data from numerous investigations support the idea that aberrant activity of D1 dopamine receptor-positive medium spiny neurons in the striatal direct pathway is associated with LID. A direct link between the real-time activity of these striatal neurons and dyskinetic symptoms remains to be established
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