Department of Psychiatry, University of California San Diego, La Jolla, CA 92093, USA.
Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA.
Int J Mol Sci. 2023 Feb 20;24(4):4204. doi: 10.3390/ijms24044204.
Previous work revealed an inverse correlation between tobacco smoking and Parkinson's disease (PD) that is associated with nicotine-induced neuroprotection of dopaminergic (DA) neurons against nigrostriatal damage in PD primates and rodent models. Nicotine, a neuroactive component of tobacco, can directly alter the activity of midbrain DA neurons and induce non-DA neurons in the substantia nigra (SN) to acquire a DA phenotype. Here, we investigated the recruitment mechanism of nigrostriatal GABAergic neurons to express DA phenotypes, such as transcription factor Nurr1 and DA-synthesizing enzyme tyrosine hydroxylase (TH), and the concomitant effects on motor function. Wild-type and α-syn-overexpressing (PD) mice treated with chronic nicotine were assessed by behavioral pattern monitor (BPM) and immunohistochemistry/in situ hybridization to measure behavior and the translational/transcriptional regulation of neurotransmitter phenotype following selective Nurr1 overexpression or DREADD-mediated chemogenetic activation. We found that nicotine treatment led to a transcriptional TH and translational Nurr1 upregulation within a pool of SN GABAergic neurons in wild-type animals. In PD mice, nicotine increased Nurr1 expression, reduced the number of α-syn-expressing neurons, and simultaneously rescued motor deficits. Hyperactivation of GABA neurons alone was sufficient to elicit de novo translational upregulation of Nurr1. Retrograde labeling revealed that a fraction of these GABAergic neurons projects to the dorsal striatum. Finally, concomitant depolarization and Nurr1 overexpression within GABA neurons were sufficient to mimic nicotine-mediated dopamine plasticity. Revealing the mechanism of nicotine-induced DA plasticity protecting SN neurons against nigrostriatal damage could contribute to developing new strategies for neurotransmitter replacement in PD.
先前的工作表明，吸烟与帕金森病（PD）呈负相关，这与尼古丁对 PD 灵长类动物和啮齿动物模型中黑质纹状体损伤的多巴胺能（DA）神经元的神经保护作用有关。烟草中的神经活性成分尼古丁可以直接改变中脑 DA 神经元的活性，并诱导黑质中的非 DA 神经元获得 DA 表型。在这里，我们研究了黑质纹状体 GABA 能神经元表达 DA 表型的募集机制，如转录因子 Nurr1 和 DA 合成酶酪氨酸羟化酶（TH），以及对运动功能的伴随影响。通过行为模式监测器（BPM）和免疫组织化学/原位杂交评估野生型和α-突触核蛋白过表达（PD）小鼠，以测量行为以及神经递质表型的翻译/转录调节，在选择性 Nurr1 过表达或 DREADD 介导的化学遗传激活后。我们发现，尼古丁处理导致野生型动物 SN GABA 能神经元中 TH 的转录和 Nurr1 的翻译上调。在 PD 小鼠中，尼古丁增加了 Nurr1 的表达，减少了α-突触核蛋白表达神经元的数量，并同时挽救了运动缺陷。单独激活 GABA 神经元就足以引起 Nurr1 的翻译上调。逆行标记显示，这些 GABA 能神经元的一部分投射到背侧纹状体。最后，GABA 神经元内的同时去极化和 Nurr1 过表达足以模拟尼古丁介导的多巴胺可塑性。揭示尼古丁诱导的 DA 可塑性保护 SN 神经元免受黑质纹状体损伤的机制可能有助于开发治疗 PD 的新策略，即神经递质替代疗法。
