Overexpression of schizophrenia susceptibility factor human complement C4Apromotes excessive synaptic loss and behavioral changes in mice

The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4Ain the brain is associated with an increased risk of schizophrenia. To investigate this genetic finding and address how C4Ashapes brain circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of C4, human C4Aand/or C4B. Human C4A bound synapses more efficiently than C4B. C4A(but not C4B) rescued the visual system synaptic refinement deficits of C4knockout mice. Intriguingly, mice without C4 had normal numbers of cortical synapses, which suggests that complement is not required for normal developmental synaptic pruning. However, overexpressing C4Ain mice reduced cortical synapse density, increased microglial engulfment of synapses and altered mouse behavior. These results suggest that increased C4A-mediated synaptic elimination results in abnormal brain circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia.