de Carvalho Michele Barboza, Teixeira-Silva Bruna, Marques Suelen Adriani, Silva Andrea Alice, Cossenza Marcelo, da Cunha Faria-Melibeu Adriana, Serfaty Claudio Alberto, Campello-Costa Paula
Laboratory of Neuroplasticity, Postgraduate Program in Neurosciences, Biology Institute, Fluminense Federal University, Niteroi, RJ, Brazil.
Laboratory of Neural Regeneration and Function, Department of Neurobiology, Federal Fluminense University, Niteroi, RJ, Brazil.
Heliyon. 2024 Jul 4;10(14):e34120. doi: 10.1016/j.heliyon.2024.e34120. eCollection 2024 Jul 30.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by selective dopaminergic loss. Non dopaminergic neurotransmitters such as glutamate are also involved in PD progression. NMDA receptor/postsynaptic density protein 95 (PSD-95)/neuronal nitric oxide synthase (nNOS) activation is involved in neuronal excitability in PD. Here, we are focusing on the evaluating these post-synaptic protein levels in the 6-OHDA model of PD. Adult male C57BL/6 mice subjected to unilateral striatal injury with 6-OHDA were assessed at 1-, 2-, or 4-weeks post-lesion. Animals were subjected to an apomorphine-induced rotation test followed by the analysis of protein content, synaptic structure, and NOx production. All biochemical analysis was performed comparing the control lesioned sides of the same animal. 6-OHDA mice exhibited contralateral rotation activity, difficulties in coordinating movements, and changes in Iba-1 and glial fibrillary acidic protein (GFAP) expression during the whole period. At one week of survival, the mice showed a shift in NMDA composition, favoring the GluN2A subunit and increased PSD95 and nNOS expression and NOx formation. After two-weeks, a decrease in the total number of synapses was observed in the lesioned side. However, the number of excitatory synapses was increased with a higher content of GluN1 subunit and PSD95. After four weeks, NMDA receptor subunits restored to control levels. Interestingly, NOx formation in the serum increased. This study reveals, for the first time, the temporal course of behavioral deficits and glutamatergic synaptic plasticity through NMDAr subunit shift. Together, these data demonstrate that dopamine depletion leads to a fine adaptive response over time, which can be used for further studies of therapeutic management adjustments with the progression of PD.
帕金森病（PD）是一种以选择性多巴胺能神经元缺失为特征的进行性神经退行性疾病。谷氨酸等非多巴胺能神经递质也参与帕金森病的进展。NMDA受体/突触后致密蛋白95（PSD - 95）/神经元型一氧化氮合酶（nNOS）的激活与帕金森病中的神经元兴奋性有关。在此，我们着重评估帕金森病6 - 羟基多巴胺（6 - OHDA）模型中这些突触后蛋白的水平。对成年雄性C57BL / 6小鼠进行单侧纹状体6 - OHDA损伤，并在损伤后1周、2周或4周进行评估。对动物进行阿扑吗啡诱导的旋转试验，随后分析蛋白质含量、突触结构和一氧化氮（NOx）生成。所有生化分析均在同一动物的对照侧和损伤侧之间进行比较。6 - OHDA小鼠在整个期间表现出对侧旋转活动、运动协调困难以及离子钙结合衔接分子1（Iba - 1）和胶质纤维酸性蛋白（GFAP）表达的变化。在存活1周时，小鼠的NMDA组成发生变化，有利于GluN2A亚基，并且PSD95和nNOS表达以及NOx形成增加。两周后，在损伤侧观察到突触总数减少。然而，兴奋性突触的数量增加，GluN1亚基和PSD95的含量更高。四周后，NMDA受体亚基恢复到对照水平。有趣的是，血清中的NOx生成增加。本研究首次揭示了行为缺陷和通过NMDAr亚基转变的谷氨酸能突触可塑性的时间进程。总之，这些数据表明多巴胺耗竭会随着时间导致精细的适应性反应，这可用于帕金森病进展过程中治疗管理调整的进一步研究。
