Striatal D1 Dopamine Neuronal Population Dynamics in a Rat Model of Levodopa-Induced Dyskinesia

BACKGROUND: 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 D(1) 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. METHODS: We examined the effect of acute levodopa treatment on striatal c-Fos expression in LID using D(1)-Cre PD rats with dyskinetic symptoms induced by chronic levodopa administration. We studied the real-time dynamics of striatal D(1) (+) neurons during dyskinetic behavior using GCaMP(6)-based in vivo fiber photometry. We also examined the effects of striatal D(1) (+) neuronal deactivation on dyskinesia in LID rats using optogenetics and chemogenetic methods. RESULTS: Striatal D(1) (+) 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 D(1) (+) neurons during dyskinetic behavior in LID rats following levodopa administration. Consistent with these observations, optogenetic deactivation of striatal D(1) (+) neurons was sufficient to inhibit most of the dyskinetic behaviors of LID animals. Moreover, chemogenetic inhibition of striatal D(1) (+) neurons delayed the onset of dyskinetic behavior after levodopa administration. CONCLUSION: Our data demonstrated that aberrant activity of striatal D(1) (+) neuronal population was causally linked with real-time dyskinetic symptoms in LID rats.