WITHDRAWN: Complement C3-dependent glutamatergic synapse elimination in the developing hippocampus is region- and synapse-specific

Abstract

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.

Complement Dependent Synaptic Reorganisation During Critical Periods of Brain Development and Risk for Psychiatric Disorder

“…Nonetheless, the changes described were selective to CA3 but not CA1, although it was not associated with a loss of Homer + puncta, but instead VGLUT2+ puncta were preferentially reduced. This is supported by other observations of VGLUT2+ synapse specific pruning (Salter et al, 2020) albeit this was observed at PND 16-18 in the CA1 region, suggesting the CA1 region may undergo pruning earlier than CA3. These differences in pruning may be linked to known distinctions in microglial reactivity in subregions of the hippocampus (Vinet et al, 2012).…”

Prenatal environmental stressors impair postnatal microglia function and adult behavior in males

“…Microglial activation and phagocytosis of debris in the brain is in part mediated through the complement system via the activation of CR3 (CD11b/ CD18) through opsonized proteins such as iC3b (Borucki et al, 2020). Several laboratories have demonstrated that developmental elimination of VGlut2+ synapses can be mediated by this same complement-dependent pathway (Salter et al, 2020;Schafer et al, 2012;Stevens et al, 2007). NIF, a glycoprotein produced by a canine hookworm, is a selective antagonist of the CR3-CD11b subunit, preventing the recognition of its endogenous ligands (Rieu et al, 1994).…”

Transcriptomic analysis of dorsal and ventral subiculum after induction of acute seizures by electric stimulation of the perforant pathway in rats

“…The C3 is one of the most abundant molecules of the complement system (Stephan et al, 2012). In the CSN, the complement system participates in synaptic pruning (Hua & Smith, 2004; Janeway Jr et al, 2001; Stephan et al, 2012), and in the hippocampus, C3 might be associated with the pruning of glutamatergic synapses (Perez‐Alcazar et al, 2014; Salter et al, 2020).…”