Lupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory

Kelvin Chan, Jacquelyn Nestor, Tomás S. Huerta, Noele Certain, Gabrielle Moody, Czeslawa Kowal, Patricio T. Huerta, Bruce T. Volpe, Betty Diamond () and Lonnie P. Wollmuth ()
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Kelvin Chan: Graduate Program in Neuroscience, Stony Brook University
Jacquelyn Nestor: Donald & Barbara Zucker School of Medicine, Hofstra University
Tomás S. Huerta: Donald & Barbara Zucker School of Medicine, Hofstra University
Noele Certain: Department of Neurobiology & Behavior, Stony Brook University
Gabrielle Moody: Department of Neurobiology & Behavior, Stony Brook University
Czeslawa Kowal: Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, Feinstein Institute for Medical Research, Northwell Health
Patricio T. Huerta: Donald & Barbara Zucker School of Medicine, Hofstra University
Bruce T. Volpe: Center for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health
Betty Diamond: Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, Feinstein Institute for Medical Research, Northwell Health
Lonnie P. Wollmuth: Department of Neurobiology & Behavior, Stony Brook University

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract Patients with Systemic lupus erythematosus (SLE) experience various peripheral and central nervous system manifestations including spatial memory impairment. A subset of autoantibodies (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.

Date: 2020
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DOI: 10.1038/s41467-020-15224-w

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