Activity-dependent synapse elimination requires caspase-3 activation
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Abstract
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.
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Synaptogenesis is initiated when axonal growth cones, extending from developing neurons, encounter their target cells and establish adhesive interactions.
“Synaptogenesis, the formation of new synapses, is initiated when axonal growth cones, extending from developing neurons, encounter their target cells and establish adhesive interactions [49,73,74].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [73]
Without caspase activity, microglia fail to recognize and eliminate inactive synapses, which is critical for circuit refinement.
“Without caspase activity, microglia fail to recognize and eliminate inactive synapses, which is critical for circuit refinement [73,81].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [73]
Microglia-mediated synapse elimination strictly requires the activation of caspase-3 within the neuronal postsynaptic compartment.
“It has been discovered that this process strictly requires the activation of caspase-3 within the neuronal postsynaptic compartment.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [73]
Initial contact triggers a cascade of intracellular signaling events that lead to the recruitment and organization of presynaptic and postsynaptic components.
“This initial contact triggers a cascade of intracellular signaling events that lead to the recruitment and organization of presynaptic and postsynaptic components.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [73]
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References 70 · Cited by 5
- Authors
- Yu, Z., Gutu, A., Kim, N., & O'Shea, E. K.
- Affiliations
- Howard Hughes Medical Institute (US)
- Janelia Research Campus, Howard Hughes Medical Institute
- Corresponding author
- Yu, Zhou
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2025-06-10
- Volume
- 13
- ISSN
- 2050-084X (ISSN-L)
- OpenAlex
- W4411186035
- Cited by
- 5
- References
- 70
- Citations by year
- 2026: 5
- FWCI
- 1.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- caspase-3, synaptic pruning, visual pathway development, spontaneous neuronal activity, Alzheimer's disease, amyloid-beta, synaptic loss, neurodegeneration, synaptic transmission inhibition
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