Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK.
J Neurosci. 2010 Feb 17;30(7):2623-35. doi: 10.1523/JNEUROSCI.5115-09.2010.
Synaptic activity promotes resistance to diverse apoptotic insults, the mechanism behind which is incompletely understood. We show here that a coordinated downregulation of core components of the intrinsic apoptosis pathway by neuronal activity forms a key part of the underlying mechanism. Activity-dependent protection against apoptotic insults is associated with inhibition of cytochrome c release in most but not all neurons, indicative of anti-apoptotic signaling both upstream and downstream of this step. We find that enhanced firing activity suppresses expression of the proapoptotic BH3-only member gene Puma in a NMDA receptor-dependent, p53-independent manner. Puma expression is sufficient to induce cytochrome c loss and neuronal apoptosis. Puma deficiency protects neurons against apoptosis and also occludes the protective effect of synaptic activity, while blockade of physiological NMDA receptor activity in the developing mouse brain induces neuronal apoptosis that is preceded by upregulation of Puma. However, enhanced activity can also confer resistance to Puma-induced apoptosis, acting downstream of cytochrome c release. This mechanism is mediated by transcriptional suppression of apoptosome components Apaf-1 and procaspase-9, and limiting caspase-9 activity, since overexpression of procaspase-9 accelerates the rate of apoptosis in active neurons back to control levels. Synaptic activity does not exert further significant anti-apoptotic effects downstream of caspase-9 activation, since an inducible form of caspase-9 overrides the protective effect of synaptic activity, despite activity-induced transcriptional suppression of caspase-3. Thus, suppression of apoptotic gene expression may synergize with other activity-dependent events such as enhancement of antioxidant defenses to promote neuronal survival.
突触活动促进抵抗多种凋亡损伤，其背后的机制尚未完全理解。我们在这里表明，神经元活动协调下调内在凋亡途径的核心组成部分是潜在机制的关键部分。活性依赖性对凋亡损伤的保护与大多数但不是所有神经元中细胞色素 c 释放的抑制有关，这表明在这一步骤的上下游都存在抗凋亡信号。我们发现，增强的放电活性以 NMDA 受体依赖性、p53 非依赖性方式抑制促凋亡 BH3 仅成员基因 Puma 的表达。Puma 的表达足以诱导细胞色素 c 的丧失和神经元凋亡。Puma 缺陷可保护神经元免受凋亡，也可阻断突触活动的保护作用，而在发育中的小鼠大脑中阻断生理 NMDA 受体活性会诱导 Puma 上调之前的神经元凋亡。然而，增强的活性也可以赋予对 Puma 诱导的凋亡的抗性，作用于细胞色素 c 释放的下游。这种机制是通过转录抑制凋亡体成分 Apaf-1 和 procaspase-9 以及限制 caspase-9 活性来介导的，因为 procaspase-9 的过表达会加速活性神经元中凋亡的速率回到对照水平。突触活动在 caspase-9 激活的下游不会发挥进一步的显著抗凋亡作用，因为诱导型 caspase-9 尽管活性诱导的 caspase-3 转录抑制，但会取代突触活动的保护作用。因此，抑制凋亡基因表达可能与其他活性依赖性事件（如增强抗氧化防御）协同作用，以促进神经元存活。
