Objective: The present study explored whether altered activity of external globus pallidus (GPe) neurons contributes to the development of motor deficits of Parkinson’s disease (PD).

Background: Motor symptoms of PD have been largely attributed to the loss of nigrostriatal dopaminergic neurons and the subsequent dysfunction of cortico-basal-ganglia (CBG) network. Recent electrophysiological and anatomical studies suggest that reduced GPe activity may be a key mechanism contributing to the CBG network dysfunction because it sends projections to all BG nuclei. Yet, behavioural evidence supporting this view are scarce and reported data are controversial.

Method: We used an optogenetic approach and unilateral 6-hydroxydopamine (6-OHDA) nigrostriatal dopaminergic lesion model of PD to investigate the contribution of GPe to the development of motor deficits (spontaneous circling, forelimb akinesia and locomotor hypoactivity). An inhibitory opsin iC++ was expressed in all GPe neurons to verify whether global GPe photoinhibition in normal C57BL/6J (BL6) mice could reproduce motor deficits produced by 6-OHDA lesions. The excitatory opsin, channelrhodopsin-2, was then expressed in GPe neurons to investigate the impact of global GPe photostimulations on expression of motor deficits in lesioned BL6 mice. Then, transgenic parvalbumin (PV)-Cre mice were used to selectively photostimulate PV-expressing neurons that preferentially innervate BG output structures.

Results: Unilateral 6-OHDA lesions induced the expected pattern of motor deficits. Unilateral photoinhibition of GPe induced only few ipsilateral rotations and bilateral photoinhibition was without effect on spontaneous locomotor behaviour, indicating that reducing GPe activity in normal mice does not reproduce parkinsonian motor features. Global GPe photostimulation ameliorated the various motor deficits produced by 6-OHDA lesion, a beneficial effect obtained at stimulation parameters ineffective in control non-lesioned mice. Interestingly, selective photostimulation of GPe PV-expressing neurons, was sufficient for restoring all motor deficits.

Conclusion: Collectively, these findings support the central role of GPe in the pathophysiology of PD and suggest that alterated GPe activity, namely hypoactivity of PV-neurons, may be a key mechanism underlying development of motor deficits.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/contribution-of-external-globus-pallidus-to-motor-deficits-of-parkinsons-disease-optogenetic-studies-in-murine-model/