Selective dendritic susceptibility to bioenergetic, excitotoxic and redox perturbations in cortical neurons.
Selective dendritic susceptibility to bioenergetic, excitotoxic and redox perturbations in cortical neurons.
复制标题
DOI：
10.1016/j.bbamcr.2014.12.021
复制
发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Hardingham GE
中科院分区：
文献类型：
--
作者：
Hasel P;Mckay S;Qiu J;Hardingham GE
神经退行性和神经系统疾病的特征通常是在神经元死亡之前树突的病理改变。氧化应激、能量不足和兴奋性毒性与许多这类疾病有关，这表明树突对这些情况有潜在的脆弱性。在这里，我们实时研究了初级皮层神经元对这些类型挑战的树突和躯体反应。使用细胞内氧化还原电位的遗传编码指标（Grx1-roGFP2），我们发现，与体细胞相比，树突区域在亚致死ROS暴露下表现出更剧烈的氧化还原电位波动，并且处于基本更氧化的状态。我们还研究了树突和体细胞区域对兴奋毒性NMDA受体活性的反应。树突区和体细胞区都经历了类似的细胞质Ca2+增加。有趣的是，虽然线粒体Ca2+摄取和初始线粒体去极化在两个区域相似，但继发性延迟线粒体去极化在树突中要弱得多，这可能是NADH消耗较少的结果。尽管如此，树突区域的ATP水平下降得更快。最后，我们研究了树突区和躯体区对高能量动作电位爆发活动的反应。爆发活动触发PDH去磷酸化，增加氧气消耗和细胞NADH:NAD比率。与体细胞区相比，树突区表现出较小的线粒体Ca2+摄取程度，较低的NADH诱导率和较大的ATP水平降低。总的来说，这些数据表明，初级神经元的树突区域比细胞体更容易受到更大的能量和氧化还原波动的影响，这可能导致与疾病相关的树突损伤。这篇文章是《第十三届欧洲钙研讨会》特刊的一部分。在氧化损伤后，树突表现出比体细胞更大的氧化还原电位变化。在兴奋性毒性过程中，树突状线粒体去极化比体细胞线粒体少。然而，在兴奋性毒性期间，ATP在树突区域下降得更快。能量要求高的AP爆发诱导适应性代谢反应。这些反应在树突中较弱，ATP水平受到更强烈的抑制。
Neurodegenerative and neurological disorders are often characterised by pathological changes to dendrites, in advance of neuronal death. Oxidative stress, energy deficits and excitotoxicity are implicated in many such disorders, suggesting a potential vulnerability of dendrites to these situations. Here we have studied dendritic vs. somatic responses of primary cortical neurons to these types of challenges in real-time. Using a genetically encoded indicator of intracellular redox potential (Grx1-roGFP2) we found that, compared to the soma, dendritic regions exhibited more dramatic fluctuations in redox potential in response to sub-lethal ROS exposure, and existed in a basally more oxidised state. We also studied the responses of dendritic and somatic regions to excitotoxic NMDA receptor activity. Both dendritic and somatic regions experienced similar increases in cytoplasmic Ca2+. Interestingly, while mitochondrial Ca2+ uptake and initial mitochondrial depolarisation were similar in both regions, secondary delayed mitochondrial depolarisation was far weaker in dendrites, potentially as a result of less NADH depletion. Despite this, ATP levels were found to fall faster in dendritic regions. Finally we studied the responses of dendritic and somatic regions to energetically demanding action potential burst activity. Burst activity triggered PDH dephosphorylation, increases in oxygen consumption and cellular NADH:NAD ratio. Compared to somatic regions, dendritic regions exhibited a smaller degree of mitochondrial Ca2+ uptake, lower fold-induction of NADH and larger reduction in ATP levels. Collectively, these data reveal that dendritic regions of primary neurons are vulnerable to greater energetic and redox fluctuations than the cell body, which may contribute to disease-associated dendritic damage. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. Dendrites exhibit a greater shift in redox potential than the soma, following an oxidative insult. Dendritic mitochondria depolarise less than somatic ones during excitotoxicity. Nevertheless ATP falls faster in dendritic regions during excitotoxicity. Energetically demanding AP bursting induces adaptive metabolic responses. These responses are weaker in dendrites, and ATP levels are suppressed more strongly.