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The Classical Complement Pathway Mediates Microglia-Dependent Remodeling of Spinal Motor Circuits during Development
Aleksandra Vukojicic1, Nicolas Delestrée1, Emily V Fletcher1
1Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
Cell Reports
|December 5, 2019
Summary
The complement protein C1q is crucial for refining motor circuits during development and is implicated in spinal muscular atrophy (SMA) by tagging synapses for elimination. Inhibiting C1q or microglia improves synapse health and behavior in SMA mice.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Spinal motor circuit refinement and synapse maintenance mechanisms are not well understood.
- Molecular basis of synaptic dysfunction in developmental neurodegenerative diseases remains unclear.
Purpose of the Study:
- To investigate the role of complement protein C1q in sensory-motor circuit refinement during normal development.
- To elucidate the molecular mechanisms underlying synaptic dysfunction and elimination in spinal muscular atrophy (SMA).
Main Methods:
- Demonstrated the requirement of C1q for normal circuit refinement.
- Showed C1q's role in tagging vulnerable synapses in SMA.
- Investigated the classical complement pathway and microglia-mediated elimination in SMA.
Main Results:
- C1q is essential for sensory-motor circuit refinement in typical development.
- C1q tags synapses in SMA, initiating complement pathway activation and microglia-mediated elimination.
- Pharmacological C1q inhibition or microglia depletion rescued synapse number and function, improving SMA mouse behavior.
Conclusions:
- The classical complement pathway is vital for refining developing motor circuits.
- Aberrant activation of the classical complement pathway contributes to motor neuron disease, specifically SMA.
- Targeting C1q or microglia presents a potential therapeutic strategy for SMA.
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