Nonapoptotic caspase-3 guides C1q-dependent synaptic phagocytosis by microglia
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 establi...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56342-7 |
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| _version_ | 1832585574747209728 |
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| author | Megumi Andoh Natsuki Shinoda Yusuke Taira Tasuku Araki Yuka Kasahara Haruki Takeuchi Masayuki Miura Yuji Ikegaya Ryuta Koyama |
| author_facet | Megumi Andoh Natsuki Shinoda Yusuke Taira Tasuku Araki Yuka Kasahara Haruki Takeuchi Masayuki Miura Yuji Ikegaya Ryuta Koyama |
| author_sort | Megumi Andoh |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-7e58161ad1354e44bd046e04cb7ae674 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-7e58161ad1354e44bd046e04cb7ae6742025-01-26T12:42:54ZengNature PortfolioNature Communications2041-17232025-01-0116111810.1038/s41467-025-56342-7Nonapoptotic caspase-3 guides C1q-dependent synaptic phagocytosis by microgliaMegumi Andoh0Natsuki Shinoda1Yusuke Taira2Tasuku Araki3Yuka Kasahara4Haruki Takeuchi5Masayuki Miura6Yuji Ikegaya7Ryuta Koyama8Department of Translational Neurobiology, National Institute of Neuroscience, National Center of Neurology and PsychiatryDepartment of Genetics, Graduate School of Pharmaceutical Sciences, The University of TokyoDepartment of Genetics, Graduate School of Pharmaceutical Sciences, The University of TokyoLaboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of TokyoLaboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of TokyoLaboratory of Molecular Neurobiology, Department of Biophysics and Biochemistry, The University of TokyoDepartment of Genetics, Graduate School of Pharmaceutical Sciences, The University of TokyoLaboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of TokyoDepartment of Translational Neurobiology, National Institute of Neuroscience, National Center of Neurology and PsychiatryAbstract 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.https://doi.org/10.1038/s41467-025-56342-7 |
| spellingShingle | Megumi Andoh Natsuki Shinoda Yusuke Taira Tasuku Araki Yuka Kasahara Haruki Takeuchi Masayuki Miura Yuji Ikegaya Ryuta Koyama Nonapoptotic caspase-3 guides C1q-dependent synaptic phagocytosis by microglia Nature Communications |
| title | Nonapoptotic caspase-3 guides C1q-dependent synaptic phagocytosis by microglia |
| title_full | Nonapoptotic caspase-3 guides C1q-dependent synaptic phagocytosis by microglia |
| title_fullStr | Nonapoptotic caspase-3 guides C1q-dependent synaptic phagocytosis by microglia |
| title_full_unstemmed | Nonapoptotic caspase-3 guides C1q-dependent synaptic phagocytosis by microglia |
| title_short | Nonapoptotic caspase-3 guides C1q-dependent synaptic phagocytosis by microglia |
| title_sort | nonapoptotic caspase 3 guides c1q dependent synaptic phagocytosis by microglia |
| url | https://doi.org/10.1038/s41467-025-56342-7 |
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