Non-apoptotic function of casapses in synapses

今年，我们揭示了长期抑郁症（LTD），线粒体和半胱天冬酶之间的关系。在这项研究中，我们表明，通过线粒体激活caspase-3实际上是需要长期抑郁症（LTD）和AMPA受体GluR 2在小鼠海马神经元的内化。我们报告，调节因子和凋亡的执行者在突触可塑性的分子机制中发挥作用。我们仔细研究了线粒体途径，这是由caspase-9和caspase-3介导的，作为LTD的重要组成部分，而不是LTP。我们发现，caspase-3敲除海马切片在LTD中有缺陷，而LTP不受影响。这是令人信服的证据，证明caspase-3在突触修饰的一种形式中具有特异性。线粒体信号通路在LTD中的重要性与其在诱导型GluR 2 AMPA受体内化中的关键作用有关。Caspase-3和-9对LTD和GluR 2的运输至关重要，但对LTP则不然。此外，短期谷氨酸受体刺激足以诱导AMPA受体再分布和突触修饰导致caspase-3激活，这是短暂的和温和的，与传统的因素，导致大量的细胞凋亡。 这种由短时间谷氨酸受体刺激引起的半胱天冬酶-3的轻度激活与细胞死亡增加无关，这是半胱天冬酶-3不可避免地导致细胞凋亡的一个强有力的指标。据信，神经元的复杂形态可以允许半胱天冬酶的局部激活，使得棘和树突可以被靶向用于功能磨损和结构消除，而不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.