The Classical Complement Pathway Mediates Microglia-Dependent Remodeling of Spinal Motor Circuits during Development and in SMA

Abstract

SUMMARY 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.

WITHDRAWN: Complement C3-dependent glutamatergic synapse elimination in the developing hippocampus is region- and synapse-specific

“…Subsequently, complement has been found to mediate developmental synaptic pruning in other regions of the CNS including excitatory synapses in the olfactory bulb (Lehmann et al, 2018) and spinal cord (Vukojicic et al, 2019) as well as dopamine receptors in the nucleus accumbens (Kopec et al, 2018).…”

Synaptic Plasticity on Motoneurons After Axotomy: A Necessary Change in Paradigm

“…This conclusion was first derived from analyses of injuries in 5-8 days old kittens (Mendell and Scott, 1975). We now know that the first week after birth is a critical period for the developmental maturation of this input (Mentis et al, 2006;Siembab et al, 2010;Vukojicic et al, 2019) introducing significant interpretation confounds. When Ia EPSP recovery was studied in adult cats the results depend on the type of injury-inducing axotomy and the postsynaptic motoneuron tested.…”

“…The mechanism by which activated ventral microglia recognizes the spinal projections of Ia afferents injured in the periphery is unknown. During normal development, microgliadependent synaptic pruning of excess VGLUT1(Ia/II) synapses occurs at specific postnatal critical periods through C1q opsonization (Vukojicic et al, 2019). C1q targets ineffective or silent synapses, and an exaggeration of this mechanism was proposed to be responsible for the loss of Ia afferent inputs on motoneurons in a mouse model of spinal muscular atrophy (Mentis et al, 2011;Vukojicic et al, 2019).…”

“…During normal development, microgliadependent synaptic pruning of excess VGLUT1(Ia/II) synapses occurs at specific postnatal critical periods through C1q opsonization (Vukojicic et al, 2019). C1q targets ineffective or silent synapses, and an exaggeration of this mechanism was proposed to be responsible for the loss of Ia afferent inputs on motoneurons in a mouse model of spinal muscular atrophy (Mentis et al, 2011;Vukojicic et al, 2019). C1q removal did not alter synapse stripping after nerve injury in adult mice (Berg et al, 2012), but this study did not analyze VGLUT1(Ia/II) synaptic plasticity.…”

C1q Regulates Horizontal Cell Neurite Confinement in the Outer Retina

“…Work over the past 15 years has established that the central nervous system (CNS) can leverage complement to control synapse elimination during development and disease (Stevens et al, 2007;Chu et al, 2010;Bialas and Stevens, 2013;Hong et al, 2016). Deletion of C1q, the initiating complement pathway signaling molecule, results in delayed refinement of the dorsolateral geniculate nucleus of the thalamus and causes defects in the development of spinal motor circuits through altered microglia-mediated removal of excess neurites and synapses (Stevens et al, 2007;Vukojicic et al, 2019). C1q-mediated synapse removal has also been implicated in Alzheimer's disease and in cognitive defects following neurotropic virus infection (Hong et al, 2016;Kunnakkadan et al, 2019).…”