1 Department of Physiology and Pathophysiology and Institute of Neuroscience, School of Basic Medical Sciences, Xi’an Jiao Tong University Health Science Center, Xi’an 710061, China
2 Department of Clinical Medicine, Xi’an Jiao Tong University Health Science Center, Xi’an 710061, China
3 Department of Rehabilitation Medicine, The Second Affiliated Hospital of Xi’an Jiao Tong University, Xi’an 710004, China
4 Department of Medical Imaging and Nuclear Medicine, The First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an 710061, China
Abstract
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 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 pallidus externa (GPe) neurons in a rat model of LID. Intrastriatal administration of raclopride, a D2R antagonist, significantly inhibited dyskinetic behavior, while intrastriatal administration of pramipexole, a D2-like receptor agonist, yielded aggravation of dyskinesia in LID rats. Fiber photometry 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 demonstrate that the aberrant activity of striatal D2R+ neurons and downstream GPe neurons is a decisive mechanism mediating dyskinetic symptoms in LID rats.
Keywords
Levodopa; Dyskinesia; Parkinson’s disease; D2 receptor; Fiber photometry; Optogenetics
