Local Pruning of Dendrites and Spines by Caspase-3-Dependent and Proteasome-Limited Mechanisms
Local Pruning of Dendrites and Spines by Caspase-3-Dependent and Proteasome-Limited Mechanisms
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DOI：
10.1523/jneurosci.3121-13.2014
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发表时间：
2014-01-29
影响因子：
5.3
通讯作者：
Sheng, Morgan
中科院分区：
文献类型：
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作者：
Ertuerk, Ali;Wang, Yuanyuan;Sheng, Morgan
突触丢失在发育过程中正常发生，在神经退行性疾病中则是病理性的。长时程抑制（一种被认为与突触消除相关的生理现象）需要半胱天冬酶 - 3和细胞凋亡的线粒体途径。在此，我们表明半胱天冬酶 - 3的活性对于调节树突棘密度和树突形态至关重要，并且可以在神经元内局部发挥作用。通过对线粒体 KillerRed进行光刺激，我们在培养的神经元特定树突区域诱导了半胱天冬酶 - 3的活性。在光刺激区域内，树突棘的局部消除和树突回缩以半胱天冬酶 - 3依赖的方式发生，且未诱导细胞死亡。然而，对凋亡抑制蛋白或蛋白酶体功能的药理抑制会导致神经元死亡，这表明半胱天冬酶的激活在空间上受到这些细胞凋亡“分子刹车”的限制。半胱天冬酶 - 3基因敲除小鼠的树突棘密度增加，微小兴奋性突触后电流改变，证实了半胱天冬酶 - 3在体内对树突棘调节的生理作用。
Synapse loss occurs normally during development and pathologically during neurodegenerative disease. Long-term depression, a proposed physiological correlate of synapse elimination, requires caspase-3 and the mitochondrial pathway of apoptosis. Here, we show that caspase-3 activity is essential-and can act locally within neurons-for regulation of spine density and dendrite morphology. By photostimulation of Mito-KillerRed, we induced caspase-3 activity in defined dendritic regions of cultured neurons. Within the photostimulated region, local elimination of dendritic spines and dendrite retraction occurred in a caspase-3-dependent manner without inducing cell death. However, pharmacological inhibition of inhibitor of apoptosis proteins or proteasome function led to neuronal death, suggesting that caspase activation is spatially restricted by these "molecular brakes" on apoptosis. Caspase-3 knock-out mice have increased spine density and altered miniature EPSCs, confirming a physiological involvement of caspase-3 in the regulation of spines in vivo.