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

Area of Science:

• Neuroscience
• Cell Biology
• Immunology

Background:

• Caspases traditionally mediate programmed cell death (apoptosis) in developing neurons.
• The precise role of caspases outside of apoptosis, particularly at synapses, remains less understood.

Purpose of the Study:

• To investigate the nonapoptotic function of caspase-3 activation at presynapses.
• To elucidate the mechanism by which caspase-3 activation influences microglial synaptic phagocytosis and neuronal circuit remodeling.

Main Methods:

• Utilized a novel mouse-derived culture system for real-time, spatiotemporal observation of synaptic caspase-3.
• Employed high-resolution live imaging to visualize synapse-microglia interactions.
• Investigated the role of complement pathways and microglial complement receptors.

Main Results:

• Increased neuronal activity triggers localized, nonapoptotic caspase-3 activation at presynapses.
• Caspase-3 activation facilitates complement-mediated synaptic tagging, guiding synapse-selective microglial phagocytosis.
• Activity-dependent caspase-3 activation at inhibitory synapses increases seizure susceptibility in mice, reversible by depleting microglial complement receptors.

Conclusions:

• Localized, nonapoptotic caspase-3 activity is a key regulator of microglial synaptic phagocytosis.
• This pathway plays a significant role in activity-dependent synaptic remodeling and influences neurological conditions like seizures.