Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Translational research division, German Center for Neurodegenerative Diseases (DZNE), Munich, 81377, Germany.
Sci Rep. 2019 Mar 19;9(1):4857. doi: 10.1038/s41598-019-41091-7.
Dopamine (DA) release in striatum is functionally segregated across a dorsolateral/ventromedial axis. Interestingly, nigrostriatal DA signaling disruption in Parkinson's disease (PD) preferentially affects the dorsolateral striatum. The relationship between afferent presynaptic calcium transients (PreCaTs) in DA terminals and DA release in dorsolateral (Caudato-Putamen, DLS) and ventromedial (Nucleus Accumbens Shell, VS) striatal subregions was examined by ex vivo real-time dual-recording in conditional transgenic mice expressing the calcium indicator protein GCaMP3. In DLS, minimal increases in cytosolic calcium trigger steep DA release while PreCaTs and DA release in VS both were proportional to the number of pulses in burst stimulation. Co-expressing α-synuclein with the Parkinson's disease (PD)-associated A53T mutation and GCaMP3 in midbrain DA neurons revealed augmented cytosolic steady state and activity-dependent intra-terminal calcium levels preferentially in DLS, as well as hyperactivation and enhanced expression of N-type calcium channels. Thus, unbalanced calcium channel activity is a presynaptic mechanism to consider in the multifaceted pathogenic pathways of progressive neurodegeneration.
纹状体中的多巴胺 (DA) 释放功能沿背外侧/腹内侧轴分离。有趣的是，帕金森病 (PD) 中黑质纹状体 DA 信号的中断优先影响背外侧纹状体。通过在表达钙指示剂蛋白 GCaMP3 的条件性转基因小鼠中进行离体实时双记录，研究了 DA 末梢的传入前钙瞬变 (PreCaTs) 与背外侧 (尾壳核，DLS) 和腹内侧 (伏隔核壳，VS) 纹状体内区的 DA 释放之间的关系。在 DLS 中，细胞浆钙的微小增加引发陡峭的 DA 释放，而 PreCaTs 和 VS 中的 DA 释放都与爆发刺激中的脉冲数成正比。在中脑 DA 神经元中与帕金森病 (PD) 相关的 A53T 突变和 GCaMP3 共表达 α-突触核蛋白，发现 DLS 中细胞浆稳态和活动依赖性末梢内钙水平的增加优先增加，以及 N 型钙通道的过度激活和增强表达。因此，钙通道活性失衡是进行性神经退行性变的多方面致病途径中需要考虑的一个突触前机制。
