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Nonapoptotic caspase-3 guides C1q-dependent synaptic phagocytosis by microglia

Author

Listed:
  • Megumi Andoh

    (National Center of Neurology and Psychiatry
    The University of Tokyo)

  • Natsuki Shinoda

    (The University of Tokyo)

  • Yusuke Taira

    (The University of Tokyo)

  • Tasuku Araki

    (The University of Tokyo)

  • Yuka Kasahara

    (The University of Tokyo)

  • Haruki Takeuchi

    (The University of Tokyo)

  • Masayuki Miura

    (The University of Tokyo)

  • Yuji Ikegaya

    (The University of Tokyo
    The University of Tokyo
    National Institute of Information and Communications Technology)

  • Ryuta Koyama

    (National Center of Neurology and Psychiatry
    The University of Tokyo
    The University of Tokyo)

Abstract

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.

Suggested Citation

  • Megumi Andoh & Natsuki Shinoda & Yusuke Taira & Tasuku Araki & Yuka Kasahara & Haruki Takeuchi & Masayuki Miura & Yuji Ikegaya & Ryuta Koyama, 2025. "Nonapoptotic caspase-3 guides C1q-dependent synaptic phagocytosis by microglia," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56342-7
    DOI: 10.1038/s41467-025-56342-7
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