Inserm UMR-S 1270, Paris, France; Sorbonne University, Science and Engineering Faculty, Paris, France; Institut du Fer à Moulin, Paris, France.
Inserm UMR-S 1270, Paris, France; Sorbonne University, Science and Engineering Faculty, Paris, France; Institut du Fer à Moulin, Paris, France.
Neurobiol Dis. 2023 Sep;185:106238. doi: 10.1016/j.nbd.2023.106238. Epub 2023 Jul 24.
L-DOPA-induced dyskinesia (LID) is a frequent adverse side effect of L-DOPA treatment in Parkinson's disease (PD). Understanding the mechanisms underlying the development of these motor disorders is needed to reduce or prevent them. We investigated the role of TrkB receptor in LID, in hemiparkinsonian mice treated by chronic L-DOPA administration. Repeated L-DOPA treatment for 10 days specifically increased full-length TrkB receptor mRNA and protein levels in the dopamine-depleted dorsal striatum (DS) compared to the contralateral non-lesioned DS or to the DS of sham-operated animals. Dopamine depletion alone or acute L-DOPA treatment did not significantly increase TrkB protein levels. In addition to increasing TrkB protein levels, chronic L-DOPA treatment activated the TrkB receptor as evidenced by its increased tyrosine phosphorylation. Using specific agonists for the D1 or D2 receptors, we found that TrkB increase is D1 receptor-dependent. To determine the consequences of these effects, the TrkB gene was selectively deleted in striatal neurons expressing the D1 receptor. Mice with TrkB floxed gene were injected with Cre-expressing adeno-associated viruses or crossed with Drd1-Cre transgenic mice. After unilateral lesion of dopamine neurons in these mice, we found an aggravation of axial LID compared to the control groups. In contrast, no change was found when TrkB deletion was induced in the indirect pathway D2 receptor-expressing neurons. Our study suggests that BDNF/TrkB signaling plays a protective role against the development of LID and that agonists specifically activating TrkB could reduce the severity of LID.
左旋多巴诱导的运动障碍（LID）是帕金森病（PD）患者左旋多巴治疗的常见不良反应。为了减少或预防这些运动障碍，有必要了解其发生的机制。我们研究了 TrkB 受体在慢性左旋多巴给药治疗的半帕金森病小鼠中 LID 发展中的作用。与对侧未损伤的 DS 或假手术动物的 DS 相比，重复 10 天的左旋多巴治疗特异性增加了多巴胺耗竭的背侧纹状体（DS）中的全长 TrkB 受体 mRNA 和蛋白水平。单独的多巴胺耗竭或急性左旋多巴治疗不会显著增加 TrkB 蛋白水平。除了增加 TrkB 蛋白水平外，慢性左旋多巴治疗还激活了 TrkB 受体，这表现为其酪氨酸磷酸化增加。使用 D1 或 D2 受体的特异性激动剂，我们发现 TrkB 增加是 D1 受体依赖性的。为了确定这些影响的后果，我们在表达 D1 受体的纹状体神经元中选择性地删除了 TrkB 基因。具有 TrkB floxed 基因的小鼠被注射表达 Cre 的腺相关病毒或与 Drd1-Cre 转基因小鼠杂交。在这些小鼠的多巴胺神经元单侧损伤后，与对照组相比，我们发现轴向 LID 加重。相比之下，当在间接通路 D2 受体表达神经元中诱导 TrkB 缺失时，没有发现变化。我们的研究表明，BDNF/TrkB 信号在 LID 的发展中起保护作用，并且特异性激活 TrkB 的激动剂可能会降低 LID 的严重程度。
