Andoh Megumi, Shinoda Natsuki, Taira Yusuke, Araki Tasuku, Kasahara Yuka, Takeuchi Haruki, Miura Masayuki, Ikegaya Yuji, Koyama Ryuta
Department of Translational Neurobiology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Japan.
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Nat Commun. 2025 Jan 22;16(1):918. doi: 10.1038/s41467-025-56342-7.
Caspases are known to mediate neuronal apoptosis during brain development. However, here we show that nonapoptotic activation of caspase-3 at presynapses drives microglial synaptic phagocytosis. Real-time observation and spatiotemporal manipulation of synaptic caspase-3 in the newly established, mouse-derived culture system demonstrate that increased neuronal activity triggers localized presynaptic caspase-3 activation, facilitating synaptic tagging by complements. High-resolution live imaging reveals that caspase-3 activation promotes synapse-selective complement-dependent microglial phagocytosis without axonal shearing. Furthermore, activity-dependent caspase-3 activation at inhibitory presynapses induces microglial phagocytosis in mice and increases seizure susceptibility. This increased susceptibility is reversed by genetic depletion of microglial complement receptors. Thus, localized, nonapoptotic caspase activity guides complement-dependent microglial synaptic phagocytosis and remodels neuronal circuits.
已知半胱天冬酶在大脑发育过程中介导神经元凋亡。然而，我们在此表明，突触前半胱天冬酶-3的非凋亡激活驱动小胶质细胞的突触吞噬作用。在新建立的源自小鼠的培养系统中对突触半胱天冬酶-3进行实时观察和时空操纵表明，神经元活动增加会触发局部突触前半胱天冬酶-3激活，促进补体介导的突触标记。高分辨率实时成像显示，半胱天冬酶-3激活促进了突触选择性补体依赖性小胶质细胞吞噬作用，而不会导致轴突切断。此外，抑制性突触处的活动依赖性半胱天冬酶-3激活在小鼠中诱导小胶质细胞吞噬作用，并增加癫痫易感性。小胶质细胞补体受体的基因缺失可逆转这种增加的易感性。因此，局部的、非凋亡的半胱天冬酶活性引导补体依赖性小胶质细胞突触吞噬作用并重塑神经元回路。
