Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice
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The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement.
In
humans, greater expression of C4A in the brain is associated with an increased risk of
schizophrenia. To investigate this genetic finding and address how C4A shapes brain
circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of C4, human C4A and/or C4B. Human C4A bound synapses more efficiently than C4B. C4A (but not C4B) rescued the
visual system synaptic refinement deficits of C4 knockout 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 C4A in 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
Reference
Yilmaz, M., Yalcin, E., Presumey, J., Aw, E., Ma, M., Whelan, C. W., ... & Carroll, M. C. (2021). Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice. Nature neuroscience, 24(2), 214-224.
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