Non-apoptotic function of casapses in synapses

今年，我们揭示了长期抑郁（LTD）、线粒体和半胱天冬酶之间的关系。在这项研究中，我们发现通过线粒体激活caspase-3实际上是小鼠海马神经元长期抑郁（LTD）和AMPA受体GluR2内化所必需的。我们报道细胞凋亡的调控因子和执行者在突触可塑性的分子机制中发挥作用。我们仔细研究了由caspase-9和caspase-3介导的线粒体途径，认为它是LTD的重要组成部分，而不是LTP的重要组成部分。我们发现caspase-3敲除的海马切片在LTD中有缺陷，而LTP不受影响。这是令人信服的证据，证明caspase-3在一种形式的突触修饰中的特异性。线粒体信号通路在LTD中的重要性与其在诱导GluR2 AMPA受体内化中的关键作用有关。caspase -3和-9对LTD和GluR2的转运至关重要，但对LTP不起作用。此外，短期的谷氨酸受体刺激足以诱导AMPA受体重分布和突触修饰，导致caspase-3的激活是短暂的和轻微的，而不是传统的导致大量细胞凋亡的因素。短时间谷氨酸受体刺激引起的caspase-3的轻度激活与细胞死亡增加无关，这是一个强有力的指标，表明caspase-3并不必然导致细胞凋亡。据信，神经元的复杂形态可以允许半胱天蛋白酶的局部激活，因此脊髓和树突可以成为功能性磨损和结构消除的目标，而不会杀死细胞的其余部分。

This year, we revealed a relationship between long-term depression (LTD), mitochondria and caspases. In this study we show that activation of caspase-3 through mitochondria is actually required for long-term depresssion (LTD) and for the internalization of AMPA receptor GluR2 in mouse hippocampal neurons. We report that regulatory factors and executors of apoptosis play a role in the molecular mechanism of synaptic plasticity. We closely examined the mitochondrial pathway, which is mediated by caspase-9 and caspase-3, as being an essential part of LTD but not LTP. We show that caspase-3 knockout hippocampal slices are defective in LTD while LTP remains unaffected. This is compelling evidence for the specificity of caspase-3 in one form of synaptic modification. The importance of the mitochondrial signaling pathway in LTD is related with its critical role in inducible GluR2 AMPA receptor internalization. Caspases-3 and -9 are crucial for LTD and GluR2 trafficking, but not for LTP. In addition, short-term glutamate receptor stimulation sufficient to induce AMPA receptor redistribution and synaptic modification causes caspase-3 activation that is transient and mild, as compared with a conventional factor that cause massive apoptosis. This mild activation of caspase-3 by short-duration glutamate receptor stimulation was unrelated with increased cell death, a strong indicator that caspase-3 does not inevitably lead to apoptosis. It is believed that the complex morphology of neurons could allow for localized activation of caspases, so that spines and dendrites could be targeted for functional attrition and structural elimination without killing the rest of the cell.