Abstract
L-dopa(1-3,4-dihydroxyphenylalanine)-induced dyskinesia(LID)is a debilitating complication of dopa-mine replacement therapy for Parkinson's disease.The potential contribution of striatal D2 receptor(D2R)-positive neurons and downstream circuits in the pathophysiology of LID remains unclear.In this study,we investigated the role of striatal D2R+neurons and downstream globus pal-lidus externa(Gpe)neurons in a rat model of LID.Intras-triatal administration of raclopride,a D2R antagonist,sig-nificantly inhibited dyskinetic behavior,while intrastriatal administration of pramipexole,a D2-like receptor agonist,yielded aggravation of dyskinesia in LID rats.Fiber pho-tometry revealed the overinhibition of striatal D2R+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 D2R+ neurons or their projections in the Gpe was adequate to suppress most of the dyskinetic behaviors of LID rats.Our data demon-strate that the aberrant activity of striatal D2R+ neurons and downstream Gpe neurons is a decisive mechanism mediating dyskinetic symptoms in LID rats.
基金项目
National Natural Science Foundation of China(81671109)
National Natural Science Foundation of China(82071526)
National Natural Science Foundation of China(82071433)
Natural Science Foundation of Shaanxi Province(2021JQ-417)
万方数据