Pearlstein Edouard, Michel François J, Save Laurène, Ferrari Diana C, Hammond Constance
UMR901, Aix-Marseille UniversitéMarseille, France; Institut de Neurobiologie de la Méditerranée (INMED), Inserm UMR 901Marseille, France.
Front Cell Neurosci. 2016 Jun 23;10:168. doi: 10.3389/fncel.2016.00168. eCollection 2016.
In a preceding study, we showed that in adult pink1(-/-) mice, a monogenic animal model of Parkinson's disease (PD), striatal neurons display aberrant electrical activities that precede the onset of overt clinical manifestations. Here, we tested the hypothesis that the maturation of dopaminergic (DA) neurons of the pink1(-/-) substantia nigra compacta (SNc) follows, from early stages on, a different developmental trajectory from age-matched wild type (wt) SNc DA neurons. We used immature (postnatal days P2-P10) and young adult (P30-P90) midbrain slices of pink1(-/-) mice expressing the green fluorescent protein in tyrosine hydroxylase (TH)-positive neurons. We report that the developmental sequence of N-Methyl-D-aspartic acid (NMDA) spontaneous excitatory postsynaptic currents (sEPSCs) is altered in pink1(-/-) SNc DA neurons, starting from shortly after birth. They lack the transient episode of high NMDA receptor-mediated neuronal activity characteristic of the immature stage of wt SNc DA neurons. The maturation of the membrane resistance of pink1(-/-) SNc DA neurons is also altered. Collectively, these observations suggest that electrical manifestations occurring shortly after birth in SNc DA neurons might lead to dysfunction in dopamine release and constitute an early pathogenic mechanism of PD.
在之前的一项研究中，我们表明，在成年粉色1基因敲除（pink1(-/-)）小鼠（一种帕金森病（PD）的单基因动物模型）中，纹状体神经元在明显的临床表现出现之前就表现出异常的电活动。在此，我们检验了这样一个假设，即粉色1基因敲除小鼠黑质致密部（SNc）的多巴胺能（DA）神经元从早期开始，其发育轨迹就与年龄匹配的野生型（wt）SNc DA神经元不同。我们使用了在酪氨酸羟化酶（TH）阳性神经元中表达绿色荧光蛋白的粉色1基因敲除小鼠的未成熟（出生后第2 - 10天）和年轻成年（第30 - 90天）中脑切片。我们报告称，粉色1基因敲除小鼠SNc DA神经元中N - 甲基 - D - 天冬氨酸（NMDA）自发兴奋性突触后电流（sEPSCs）的发育序列从出生后不久就发生了改变。它们缺乏wt SNc DA神经元未成熟阶段特有的由NMDA受体介导的神经元活动的短暂高峰。粉色1基因敲除小鼠SNc DA神经元的膜电阻成熟也发生了改变。总的来说，这些观察结果表明，SNc DA神经元在出生后不久出现的电表现可能导致多巴胺释放功能障碍，并构成PD的早期致病机制。
