Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France.
Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; National Centre for Scientific Research, Institut des Maladies Neurodégénératives, Bordeaux, France; Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
Biol Psychiatry. 2016 Mar 1;79(5):345-353. doi: 10.1016/j.biopsych.2014.08.022. Epub 2014 Sep 9.
A systematic search of brain nuclei putatively involved in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson's disease shed light, notably, upon the lateral habenula (LHb), which displayed an overexpression of the ∆FosB, ARC, and Zif268 immediate-early genes only in rats experiencing abnormal involuntary movements (AIMs). We thus hypothesized that LHb might play a role in LID.
∆FosB immunoreactivity, 2-deoxyglucose uptake, and firing activity of LHb were studied in experimental models of Parkinson's disease and LID. ΔFosB-expressing LHb neurons were then targeted using the Daun02-inactivation method. A total of 18 monkeys and 55 rats were used.
LHb was found to be metabolically modified in dyskinetic monkeys and its neuronal firing frequency significantly increased in ON L-DOPA dyskinetic 6-hydroxydopamine-lesioned rats, suggesting that increased LHb neuronal activity in response to L-DOPA is related to AIM manifestation. Therefore, to mechanistically test if LHb neuronal activity might affect AIM severity, following induction of AIMs, 6-hydroxydopamine rats were injected with Daun02 in the LHb previously transfected with ß-galactosidase under control of the FosB promoter. Three days after Daun02 administration, animals were tested daily with L-DOPA to assess LID and L-DOPA-induced rotations. Inactivation of ∆FosB-expressing neurons significantly reduced AIM severity and also increased rotations. Interestingly, the dopaminergic D1 receptor was overexpressed only on the lesioned side of dyskinetic rats in LHb and co-localized with ΔFosB, suggesting a D1 receptor-mediated mechanism supporting the LHb involvement in AIMs.
This study highlights the role of LHb in LID, offering a new target to innovative treatments of LID.
系统搜索大脑核团，这些核团被认为与帕金森病中 L-3,4-二羟基苯丙氨酸（L-DOPA）诱导的运动障碍（LID）有关，特别是外侧缰核（LHb），在经历异常不自主运动（AIMs）的大鼠中，该核团显示出 ∆FosB、ARC 和 Zif268 即刻早期基因的过度表达。因此，我们假设 LHb 可能在 LID 中发挥作用。
在帕金森病和 LID 的实验模型中研究了 ∆FosB 免疫反应性、2-脱氧葡萄糖摄取和 LHb 的放电活动。然后使用 Daun02 失活方法靶向表达 ∆FosB 的 LHb 神经元。总共使用了 18 只猴子和 55 只大鼠。
在运动障碍的猴子中发现 LHb 代谢发生改变，在 ON L-DOPA 运动障碍的 6-羟多巴胺损伤大鼠中其神经元放电频率显著增加，这表明 LHb 神经元对 L-DOPA 的活性增加与 AIM 表现有关。因此，为了从机制上测试 LHb 神经元活动是否可能影响 AIM 的严重程度，在诱导 AIMs 后，将 Daun02 注入先前在 FosB 启动子控制下用 β-半乳糖苷酶转染的 LHb 中的 6-羟多巴胺大鼠中。在 Daun02 给药后 3 天，每天用 L-DOPA 对动物进行测试，以评估 LID 和 L-DOPA 诱导的旋转。失活表达 ∆FosB 的神经元显著降低了 AIM 的严重程度，同时也增加了旋转。有趣的是，在 LHb 中，多巴胺 D1 受体仅在运动障碍大鼠的损伤侧过度表达，并且与 ∆FosB 共定位，表明 D1 受体介导的机制支持 LHb 参与 AIMs。
这项研究强调了 LHb 在 LID 中的作用，为 LID 的创新治疗提供了新的靶点。
