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

The complement cascade is an innate immune pathway that, in addition to host defense against pathogens, actively maintains tissue homeostasis. Complement is necessary for synaptic pruning during development and drives aberrant synapse loss in a number of neurodegenerative disorders that affect the hippocampus. However, the physiological function of complement in hippocampal synapse development is unknown. To address this, we investigated C3 mice at P16-18. We found that VGLUT2 synapses were increased in the CA1 stratum lacunosum moleculare (SLM) and dentate gyrus molecular layer (DGML) of C3 mice compared to wildtype. Conversely, VGLUT1 synapses, inhibitory synapses and myelin were not affected in the CA1 stratum radiatum (SR), SLM or DGML of C3 mice. Finally, we found that there was a decrease in microglial phagocytic activity only in VGLUT2 regions and this correlated with the amount of VGLUT2 synapses. Our study elucidates a role of the complement cascade in regulating hippocampus synapse number with exceptional specificity for VGLUT2-containing synapses during development.