Microglia-complement interactions mediate synaptic dysfunctions in a mouse model of schizophrenia in vivo
1 German Center for Neurodegenerative diseases (DZNE), Bonn Germany
2 Institut du Fer á Moulin, INSERM 1270, Paris France
Microglia complement signaling has been shown to promote synaptic pruning during brain development, a process by which excess synapses are eliminated. High-expression variants of the complement component 4 (C4) genes constitute a major risk factor to develop schizophrenia in humans. Interestingly, convergent studies point to a loss of dendritic spines in the cortex of schizophrenic patients, which could reflect disturbances in the normal synaptic pruning processes. Likewise, over-expressing C4 in the mouse cortex leads to schizophrenia-associated phenotypes, including synapse loss. To further assess if this synapse loss is mediated by microglia complement interactions, we use a transgenic mouse line lacking the complement receptor 3 (CR3) and overexpressed C4 in the prefrontal cortex via in utero electroporation. We inspected microglia-neuron interactions via in vivo two-photon imaging at two consecutive time points during development, as well as microglia morphology and microglia engulfment. Additionally, we examined electrophysiological properties and morphological properties of pyramidal neurons in the PFC. Our results show spine loss, altered microglia contact rates at both pre and post synapses, reduced microglial motility and higher engulfment of presynaptic proteins after C4 overexpression. In the absence of the CR3 receptor spine loss was significantly elevated. Microglia motility, morphology and number of presynaptic inclusions were normalized after CR3KO. These results suggest that the effects of C4 overexpression are regulated by microglia-complement signaling and demonstrate the microglial CR3 to be necessary for recognition of complement tagged synapses. This highlights the CR3 axis as possible treatment target for cognitive disorders such as schizophrenia.