Journal Article

Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice

Yilmaz, Melis, Presumey, Jessy, Whelan, Christopher W., McCarroll, Steven A., Carroll, Michael C., Aw, Ernest, Stevens, Beth, Yalcin, Esra, Ma, Minghe

2021

Overview

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 circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia. Overexpression of complement C4A is associated with schizophrenia risk. Using a novel mouse model, Yilmaz et al. find that increased expression of C4A leads to abnormal synaptic pruning and behavior, suggesting its importance as a therapeutic target.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/51 / 14/1 / 14/19 / 14/34 / 38/109 / 38/39 / 38/91 / 631/378/2571/2577 / 631/378/371 / 64/60 / 692/699/476/1799 / 82/29 / 96/31 / 96/63 / Animal Genetics and Genomics / Animals / Behavior, Animal / Behavioral Sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Brain / Circuits / Complement / Complement (Immunology) / Complement C4 - biosynthesis / Complement C4 - genetics / Complement component C4 / Dendritic Spines - pathology / Depression - psychology / Female / Gene Dosage / Gene expression / Genetic aspects / Health aspects / Isoforms / Male / Mental disorders / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / Microglia - pathology / Nerve Net - pathology / Neural circuitry / Neurobiology / Neurological research / Neurosciences / Pruning / Psychomotor Performance / Risk factors / Schizophrenia / Schizophrenia - genetics / Schizophrenia - pathology / Schizophrenic Psychology / Susceptibility / Synapses / Synapses - pathology / Synaptic density / Synaptosomes - pathology / Therapeutic targets / Visual pathways / Visual system