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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\u2019s disease, caspase-3 deficiency protects against synapse loss induced by amyloid-\u03b2 deposition. Our results reveal caspase-3 activation as a key step in activity-dependent synapse elimination during development and synapse loss in neurodegeneration.<\/jats:p>","DOI":"10.7554\/elife.101779","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T07:25:29Z","timestamp":1729236329000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.101779","source":"Crossref","is-referenced-by-count":5,"title":["Activity-dependent synapse elimination requires caspase-3 activation"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3213-4583","authenticated-orcid":true,"given":"Zhou","family":"Yu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"publisher"}],"name":"Janelia Research Campus, Howard Hughes Medical Institute","place":["Ashburn, United 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