The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Cell. 2010 May 28;141(5):859-71. doi: 10.1016/j.cell.2010.03.053.
NMDA receptor-dependent synaptic modifications, such as long-term potentiation (LTP) and long-term depression (LTD), are essential for brain development and function. LTD occurs mainly by the removal of AMPA receptors from the postsynaptic membrane, but the underlying molecular mechanisms remain unclear. Here, we show that activation of caspase-3 via mitochondria is required for LTD and AMPA receptor internalization in hippocampal neurons. LTD and AMPA receptor internalization are blocked by peptide inhibitors of caspase-3 and -9. In hippocampal slices from caspase-3 knockout mice, LTD is abolished whereas LTP remains normal. LTD is also prevented by overexpression of the anti-apoptotic proteins XIAP or Bcl-xL, and by a mutant Akt1 protein that is resistant to caspase-3 proteolysis. NMDA receptor stimulation that induces LTD transiently activates caspase-3 in dendrites, without causing cell death. These data indicate an unexpected causal link between the molecular mechanisms of apoptosis and LTD.
N-甲基-D-天冬氨酸受体（NMDA）依赖性突触修饰，如长时程增强（LTP）和长时程抑制（LTD），对于大脑发育和功能至关重要。LTD 主要通过 AMPA 受体从突触后膜的去除来实现，但潜在的分子机制仍不清楚。在这里，我们显示通过线粒体激活 caspase-3 对于海马神经元中的 LTD 和 AMPA 受体内化是必需的。LTD 和 AMPA 受体内化被 caspase-3 和 -9 的肽抑制剂阻断。在 caspase-3 敲除小鼠的海马切片中，LTD 被消除，而 LTP 保持正常。XIAP 或 Bcl-xL 的抗凋亡蛋白的过表达以及对 caspase-3 蛋白水解具有抗性的突变 Akt1 蛋白也可防止 LTD。诱导 LTD 的 NMDA 受体刺激可瞬时激活树突中的 caspase-3，而不会导致细胞死亡。这些数据表明细胞凋亡和 LTD 的分子机制之间存在意想不到的因果关系。
