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.

大多数帕金森氏病 (PD) 患者患有左旋多巴引起的运动障碍 (LID)。除了功能失调的多巴胺能系统外，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，血清素能神经元具有合成多巴胺的潜力，这可能与纹状体内不成比例的多巴胺释放有关。我们假设，由于多巴胺能输入的减少，纹状体中的血清素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，背侧纹状体中多巴胺能纤维显着减少约 30-40%，同时黑质致密部中多巴胺能神经元减少约 50%。相比之下，5-羟色胺能纤维在背侧纹状体中的纤维密度增加了约 100%，而中缝核 (RN) 及其近端神经炎过程中的 5-羟色胺能神经元数量不受影响。此外，邻近运动皮层 M1/M2 的多巴胺能和血清素能纤维密度均保持不变。有趣的是，左旋多巴转换和多巴胺释放所需的必需酶在 RN 的血清素能神经元中表达。同时，纹状体内参与血清素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，增加的 5-羟色胺能纤维密度及其在纹状体内释放多巴胺的能力表明存在代偿性的、位点特异性的 5-羟色胺能神经发生。