Objective: This study was aimed at examining whether decreasing the baseline SPN firing frequency towards the low activity found in normal conditions reduces LID.

Background: Loss of nigrostriatal dopamine in Parkinson’s disease (PD) causes dysregulation of striatal projection neurons (SPNs), but long-term dopamine replacement fails to efficiently modulate SPNs. Recordings in animal models of chronic, advanced PD and patients have revealed significant hyperactivity widely distributed across SPNs. Hyperactive SPNs respond to dopaminergic stimulation with pathological (unstable) firing changes, which are associated with motor responses complicated by dyskinesias (LID).

Method: To test acute pharmacological reduction of the SPN activity, a selective NMDAR antagonist (LY235959) or vehicle (aCSF) as control was infused into one side of the putamen of advanced parkinsonian non-human primate (NHPs, n=3). The antagonist was infused in the “off” state, and L-Dopa methyl ester plus benserazide was injected s.c. after the infusion. To test chronic reduction of the SPN activity, the inhibitory DREADDs (designer receptor exclusively activated by designer drugs) hM4Di was expressed in the striatum of hemiparkinsonian rats. rAAV-hSyn-hM4D(Gi)-mCherry or the control virus (rAAV-hSyn-GFP) was injected into the left striatum of rats with 6-hydroxydopamine lesions of the left nigrostriatal pathway (n=9). After 4 weeks, rats received daily CNO treatment to activate DREADDs and L-Dopa to induce AIMs for 2 weeks. The whole motor response and LID or AIMs (abnormal involuntary movements) were assessed using standardized rating scales for NHP and rodents, respectively.

Results: The NMDAR antagonist infusion in parkinsonian NHPs significantly reduced LID scores on the contralateral side without affecting the antiparkinsonian action of L-Dopa (motor disability scores of “on” state). Chronic activation of inhibitory DREADDs in rats significantly reduced AIMs.

Conclusion: These results indicate that strategies to reduce the hyperactivity of SPNs may help control dyskinesias. The potential of this strategy to induce further improvements in motor responses to L-Dopa remains to be assessed.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/toning-down-spns-to-improve-motor-responses-to-dopaminergic-stimulation-in-parkinsons-disease/