Stemick Judith, Gauer Carina, Wihan Jeanette, Moceri Sandra, Xiang Wei, von Hörsten Stephan, Kohl Zacharias, Winkler Jürgen
Department of Molecular Neurology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Department of Experimental Therapy, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Brain Res. 2020 Dec 1;1748:147119. doi: 10.1016/j.brainres.2020.147119. Epub 2020 Sep 10.
The majority of patients with Parkinson's disease (PD) suffer from L-DOPA-induced dyskinesia (LID). Besides a dysfunctional dopaminergic system, changes of the serotonergic network may be linked to this severe and adverse symptom. Particularly, serotonergic neurons have the potential to synthesize dopamine, likely associated with a disproportional dopamine release within the striatum. We hypothesized that the serotonergic system is adaptively altered in the striatum due to the reduced dopaminergic input. To answer this question, we analyzed a transgenic rat PD model ubiquitously expressing human α-synuclein using a bacterial artificial chromosome. Neurite analysis showed a profound loss of dopaminergic fibers by ~30-40% within the dorsal striatum paralleled by a ~50% reduction of dopaminergic neurons in the substantia nigra pars compacta. In contrast, serotonergic fibers showed an increased fiber density in the dorsal striatum by ~100%, while the number of serotonergic neurons within the raphe nuclei (RN) and its proximal neuritic processes were unaffected. Furthermore, both the dopaminergic and serotonergic fiber density remained unchanged in the neighboring motor cortex M1/M2. Interestingly, essential enzymes required for L-DOPA turnover and dopamine release were expressed in serotonergic neurons of the RN. In parallel, the serotonergic autoreceptor levels involved in a serotonergic negative feedback loop were reduced within the striatum, suggesting a dysfunctional neurotransmitter release. Overall, the increased serotonergic fiber density with its capacity for dopamine release within the striatum suggests a compensatory, site-specific serotonergic neuritogenesis. This maladaptive serotonergic plasticity may be linked to adverse symptoms such as LIDs in PD.
大多数帕金森病（PD）患者会出现左旋多巴诱导的运动障碍（LID）。除了多巴胺能系统功能失调外，血清素能网络的变化可能与这种严重的不良症状有关。特别是，血清素能神经元有合成多巴胺的潜力，这可能与纹状体内多巴胺释放不成比例有关。我们假设，由于多巴胺能输入减少，纹状体内血清素能系统会发生适应性改变。为了回答这个问题，我们使用细菌人工染色体分析了一种普遍表达人α-突触核蛋白的转基因大鼠PD模型。神经突分析显示，背侧纹状体内多巴胺能纤维显著减少约30 - 40%，同时黑质致密部多巴胺能神经元减少约50%。相比之下，血清素能纤维在背侧纹状体内的纤维密度增加了约100%，而中缝核（RN）内血清素能神经元的数量及其近端神经突未受影响。此外，相邻的运动皮层M1/M2中的多巴胺能和血清素能纤维密度均保持不变。有趣的是，RN的血清素能神经元中表达了左旋多巴代谢和多巴胺释放所需的关键酶。同时，纹状体内参与血清素能负反馈回路的血清素能自身受体水平降低，表明神经递质释放功能失调。总体而言，纹状体内血清素能纤维密度增加及其释放多巴胺的能力表明存在代偿性的、位点特异性的血清素能神经突形成。这种适应不良的血清素能可塑性可能与PD中的LID等不良症状有关。
