Yu Zhou, Gutu Andrian, Kim Namsoo, O'Shea Erin K
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States.
Elife. 2025 Jun 10;13:RP101779. doi: 10.7554/eLife.101779.
During brain development, synapses are initially formed in excess and are later eliminated in an activity-dependent manner. Weak synapses are preferentially removed, but the mechanism linking neuronal activity to synapse removal is unclear. Here, we show that, in the developing mouse visual pathway, inhibiting synaptic transmission induces postsynaptic activation of caspase-3. Caspase-3 deficiency results in defects in synapse elimination driven by both spontaneous and experience-dependent neural activity. Notably, caspase-3 deficiency blocks activity-dependent synapse elimination, as evidenced by reduced engulfment of inactive synapses by microglia. Furthermore, in a mouse model of Alzheimer's disease, caspase-3 deficiency protects against synapse loss induced by amyloid-β deposition. Our results reveal caspase-3 activation as a key step in activity-dependent synapse elimination during development and synapse loss in neurodegeneration.
在大脑发育过程中，突触最初过度形成，随后以活动依赖的方式被消除。较弱的突触优先被清除，但将神经元活动与突触清除联系起来的机制尚不清楚。在这里，我们表明，在发育中的小鼠视觉通路中，抑制突触传递会诱导caspase-3的突触后激活。caspase-3缺陷导致由自发和经验依赖的神经活动驱动的突触消除缺陷。值得注意的是，caspase-3缺陷会阻止活动依赖的突触消除，小胶质细胞对无活性突触的吞噬减少就证明了这一点。此外，在阿尔茨海默病的小鼠模型中，caspase-3缺陷可防止由淀粉样β蛋白沉积诱导的突触丢失。我们的结果揭示了caspase-3激活是发育过程中活动依赖的突触消除和神经退行性变中突触丢失的关键步骤。
