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.

doi:10.1101/2023.09.09.556388

bioRxiv · 10.1101/2023.09.09.556388

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.

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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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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.. 2023-09-10. C4 induces pathological synaptic loss by impairing AMPAR trafficking.. https://doi.org/10.1101/2023.09.09.556388

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