Graduate Institute of Biomedical Sciences, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.
Department and Graduate Institute of Physiology, National Taiwan University, College of Medicine, Taipei, Taiwan.
Neurobiol Dis. 2024 Apr;193:106452. doi: 10.1016/j.nbd.2024.106452. Epub 2024 Feb 23.
A common adverse effect of Parkinson's disease (PD) treatment is L-dopa-induced dyskinesia (LID). This condition results from both dopamine (DA)-dependent and DA-independent mechanisms, as glutamate inputs from corticostriatal projection neurons impact DA-responsive medium spiny neurons in the striatum to cause the dyskinetic behaviors. In this study, we explored whether suppression of presynaptic corticostriatal glutamate inputs might affect the behavioral and biochemical outcomes associated with LID. We first established an animal model in which 6-hydroxydopamine (6-OHDA)-lesioned mice were treated daily with L-dopa (10 mg/kg, i.p.) for 2 weeks; these mice developed stereotypical abnormal involuntary movements (AIMs). When the mice were pretreated with the NMDA antagonist, amantadine, we observed suppression of AIMs and reductions of phosphorylated ERK1/2 and NR2B in the striatum. We then took an optogenetic approach to manipulate glutamatergic activity. Slc17a6 (vGluT2)-Cre mice were injected with pAAV5-Ef1a-DIO-eNpHR3.0-mCherry and received optic fiber implants in either the M1 motor cortex or dorsolateral striatum. Optogenetic inactivation at either optic fiber implant location could successfully reduce the intensity of AIMs after 6-OHDA lesioning and L-dopa treatment. Both optical manipulation strategies also suppressed phospho-ERK1/2 and phospho-NR2B signals in the striatum. Finally, we performed intrastriatal injections of LDN 212320 in the dyskenesic mice to enhance expression of glutamate uptake transporter GLT-1. Sixteen hours after the LDN 212320 treatment, L-dopa-induced AIMs were reduced along with the levels of striatal phospho-ERK1/2 and phospho-NR2B. Together, our results affirm a critical role of corticostriatal glutamate neurons in LID and strongly suggest that diminishing synaptic glutamate, either by suppression of neuronal activity or by upregulation of GLT-1, could be an effective approach for managing LID.
帕金森病 (PD) 治疗的常见不良反应是左旋多巴诱导的运动障碍 (LID)。这种情况是由多巴胺 (DA) 依赖性和非 DA 依赖性机制引起的，因为来自皮质纹状体投射神经元的谷氨酸输入会影响纹状体中的 DA 反应性中等棘突神经元，从而导致运动障碍行为。在这项研究中，我们探讨了抑制皮质纹状体谷氨酸前突传入是否会影响与 LID 相关的行为和生化结果。我们首先建立了一个动物模型，其中 6-羟多巴胺 (6-OHDA) 损伤的小鼠每天接受 L-多巴 (10 mg/kg，ip) 治疗 2 周；这些小鼠出现刻板的异常不自主运动 (AIMs)。当小鼠用 NMDA 拮抗剂金刚烷胺预处理时，我们观察到 AIMs 抑制以及纹状体中磷酸化 ERK1/2 和 NR2B 的减少。然后，我们采用光遗传学方法来操纵谷氨酸能活性。Slc17a6 (vGluT2)-Cre 小鼠接受 pAAV5-Ef1a-DIO-eNpHR3.0-mCherry 注射，并在 M1 运动皮层或背外侧纹状体接受光纤植入。在 6-OHDA 损伤和 L-多巴治疗后，任一光纤植入部位的光遗传学失活都可以成功降低 AIMs 的强度。两种光学操作策略还抑制了纹状体中的磷酸化 ERK1/2 和磷酸化 NR2B 信号。最后，我们在运动障碍小鼠的纹状体中注射 LDN 212320 以增强谷氨酸摄取转运体 GLT-1 的表达。LDN 212320 治疗后 16 小时，L-多巴诱导的 AIMs 减少，同时纹状体中磷酸化 ERK1/2 和磷酸化 NR2B 的水平也降低。总之，我们的结果证实了皮质纹状体谷氨酸神经元在 LID 中的关键作用，并强烈表明，通过抑制神经元活性或上调 GLT-1 来减少突触谷氨酸，可能是治疗 LID 的有效方法。
