Striatal D 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 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-Cre PD rats with dyskinetic symptoms induced by chronic levodopa administration. We studied the real-time dynamics of striatal D neurons during dyskinetic behavior using GCaMP-based fiber photometry. We also examined the effects of striatal D neuronal deactivation on dyskinesia in LID rats using optogenetics and chemogenetic methods.

RESULTS

Striatal D 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 neurons during dyskinetic behavior in LID rats following levodopa administration. Consistent with these observations, optogenetic deactivation of striatal D neurons was sufficient to inhibit most of the dyskinetic behaviors of LID animals. Moreover, chemogenetic inhibition of striatal D neurons delayed the onset of dyskinetic behavior after levodopa administration.

CONCLUSION

Our data demonstrated that aberrant activity of striatal D neuronal population was causally linked with real-time dyskinetic symptoms in LID rats.