The Dynamics of Dopamine D_(2) Receptor-Expressing Striatal Neurons and the Downstream Circuit Underlying L-Dopa-Induced Dyskinesia in Rats

L-dopa(l-3,4-dihydroxyphenylalanine)-induced dyskinesia(LID)is a debilitating complication of dopamine replacement therapy for Parkinson’s disease.The potential contribution of striatal D_(2) receptor(D2R)-positive neurons and downstream circuits in the pathophysiology of LID remains unclear.In this study,we investigated the role of striatal D_(2)R+neurons and downstream globus pallidus externa(GPe)neurons in a rat model of LID.Intrastriatal administration of raclopride,a D_(2)R antagonist,significantly inhibited dyskinetic behavior,while intrastriatal administration of pramipexole,a D_(2)-like receptor agonist,yielded aggravation of dyskinesia in LID rats.Fiber photometry revealed the overinhibition of striatal D_(2)R+neurons and hyperactivity of downstream GPe neurons during the dyskinetic phase of LID rats.In contrast,the striatal D2R+neurons showed intermittent synchronized overactivity in the decay phase of dyskinesia.Consistent with the above findings,optogenetic activation of striatal D_(2)R+neurons or their projections in the GPe was adequate to suppress most of the dyskinetic behaviors of LID rats.Our data demonstrate that the aberrant activity of striatal D_(2)R+neurons and downstream GPe neurons is a decisive mechanism mediating dyskinetic symptoms in LID rats.