Lupus auto-antibodies act as positive allosteric modulators at NMDA receptors and induce spatial memory deficits

Chan, K.; Nestor, J.; Huerta, T. S.; Certain, N.; Moody, G.; Kowal, C.; Huerta, P. T.; Volpe, B. T.; Diamond, B.; Wollmuth, L. P.

doi:10.1101/791715

bioRxiv · 10.1101/791715

Lupus auto-antibodies act as positive allosteric modulators at NMDA receptors and induce spatial memory deficits

Chan, K.·Nestor, J.·Huerta, T. S.·Certain, N.·Moody, G.·Kowal, C.·Huerta, P. T.·Volpe, B. T.·Diamond, B.·Wollmuth, L. P.

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Abstract

Patients with Systemic lupus erythematosus (SLE) experience various peripheral and central nervous system manifestations including spatial memory impairment. A subset of auto-antibodies (DNRAbs) cross-react with the GluN2A and GluN2B subunits of the NMDA receptor (NMDAR). We find that these DNRAbs act as positive allosteric modulators on NMDARs with GluN2A-containing NMDARs, even those containing a single GluN2A subunit, exhibiting a much greater sensitivity to DNRAbs than those with exclusively GluN2B. Accordingly, GluN2A-specific antagonists provide greater protection from DNRAb-mediated neuronal cell death than GluN2B antagonists. Using transgenic mice to perturb expression of either GluN2A or GluN2B in vivo, we find that DNRAb-mediated disruption of spatial memory characterized by early neuronal cell death and subsequent microglia-dependent pathologies requires GluN2A-containing NMDARs. Our results indicate that GluN2A-specific antagonists or negative allosteric modulators are strong candidates to treat SLE patients with nervous system dysfunction.

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Chan, K., Nestor, J., Huerta, T. S., Certain, N., Moody, G., Kowal, C., Huerta, P. T., Volpe, B. T., Diamond, B., Wollmuth, L. P.. 2019-10-03. Lupus auto-antibodies act as positive allosteric modulators at NMDA receptors and induce spatial memory deficits. https://doi.org/10.1101/791715

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