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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.
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