C4 induces pathological synaptic loss by impairing AMPAR trafficking.
Phadke, R. A.; Kruzich, E.; Fournier, L. A.; Brack, A.; Sha, M.; Picard, I.; Johnson, C.; Stroumbakis, D.; Salgado, M.; Liu, Y. Y.; Cruz-Martin, A.
Show abstract
During development, activation of the complement pathway, an extracellular proteolytic cascade, results in microglia-dependent synaptic elimination via complement receptor 3 (CR3). Here, we report that decreased connectivity caused by overexpression of C4 (C4-OE), a schizophrenia-associated gene, is CR3 independent. Instead, C4-OE triggers GluR1 degradation through an intracellular mechanism involving endosomal trafficking protein SNX27, resulting in pathological synaptic loss. Moreover, the connectivity deficits associated with C4-OE were rescued by increasing levels of SNX27, linking excessive complement activity to an intracellular endolysosomal recycling pathway affecting synapses.
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