期刊
CELL REPORTS
卷 29, 期 10, 页码 3087-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.11.013
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资金
- National Institute of Neurological Disorders and Stroke (NINDS), NIH [R01-NS078375]
- NIH Blueprint for Neuroscience Research, National Institute of Alcohol Abuse and Alcoholism (NIAAA)
- NINDS [R01-AA027079]
- Department of Defense [GR.10235006]
- SMA Foundation
- Project ALS
Movement is an essential behavior requiring the assembly and refinement of spinal motor circuits. However, the mechanisms responsible for circuit refinement and synapse maintenance are poorly understood. Similarly, the molecular mechanisms by which gene mutations cause dysfunction and elimination of synapses in neurodegenerative diseases that occur during development are unknown. Here, we demonstrate that the complement protein C1q is required for the refinement of sensory-motor circuits during normal development, as well as for synaptic dysfunction and elimination in spinal muscular atrophy (SMA). C1q tags vulnerable SMA synapses, which triggers activation of the classical complement pathway leading to microglia-mediated elimination. Pharmacological inhibition of C1q or depletion of microglia rescues the number and function of synapses, conferring significant behavioral benefit in SMA mice. Thus, the classical complement pathway plays critical roles in the refinement of developing motor circuits, while its aberrant activation contributes to motor neuron disease.
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