Aix-Marseille Université, CNRS, LNC (UMR 729), 13331 Marseille, France.
Int J Mol Sci. 2023 Apr 27;24(9):7935. doi: 10.3390/ijms24097935.
Excessive inhibition of the external globus pallidus (GPe) by striatal GABAergic neurons is considered a central mechanism contributing to motor symptoms of Parkinson's disease (PD). While electrophysiological findings support this view, behavioral studies assessing the beneficial effects of global GPe activations are scarce and the reported results are controversial. We used an optogenetic approach and the standard unilateral 6-hydroxydopamine nigrostriatal dopamine (DA) lesion model of PD to explore the effects of GPe photostimulation on motor deficits in mice. Global optogenetic GPe inhibition was used in normal mice to verify whether it reproduced the typical motor impairment induced by DA lesions. GPe activation improved ipsilateral circling, contralateral forelimb akinesia, locomotor hypoactivity, and bradykinesia in 6-OHDA-lesioned mice at ineffective photostimulation parameters (532 nm, 5 Hz, 3 mW) in normal mice. GPe photoinhibition (450 nm, 12 mW) had no effect on locomotor activity and forelimb use in normal mice. Bilateral photoinhibition (450 nm, 6 mW/side) reduced directed exploration and improved working memory performances indicating that recruitment of GPe in physiological conditions may depend on the behavioral task involved. Collectively, these findings shed new light on the functional role of GPe and suggest that it is a promising target for neuromodulatory restoration of motor deficits in PD.
纹状体 GABA 能神经元对外侧苍白球（GPe）的过度抑制被认为是导致帕金森病（PD）运动症状的核心机制。虽然电生理研究结果支持这一观点，但评估 GPe 整体激活的有益效果的行为研究却很少，且报道的结果存在争议。我们使用光遗传学方法和标准的单侧 6-羟多巴胺黑质纹状体多巴胺（DA）损伤 PD 模型，来研究 GPe 光刺激对小鼠运动缺陷的影响。我们在正常小鼠中使用全局光遗传学 GPe 抑制来验证其是否能重现由 DA 损伤引起的典型运动障碍。在正常小鼠中，无效光刺激参数（532nm、5Hz、3mW）下，GPe 激活改善了 6-OHDA 损伤小鼠的同侧转圈、对侧前肢运动迟缓、运动活动减少和运动迟缓。在正常小鼠中，GPe 光抑制（450nm、12mW）对运动活动和前肢使用没有影响。双侧光抑制（450nm、6mW/侧）减少了定向探索，改善了工作记忆表现，表明 GPe 在生理条件下的募集可能取决于所涉及的行为任务。总之，这些发现为 GPe 的功能作用提供了新的认识，并表明它是一种有前途的治疗 PD 运动缺陷的神经调节靶点。
