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

• Published in: Nature communications 2020-03, Vol.11 (1), p.1403-11, Article 1403
• Main Authors: Chan, Kelvin, Nestor, Jacquelyn, Huerta, Tomás S., Certain, Noele, Moody, Gabrielle, Kowal, Czeslawa, Huerta, Patricio T., Volpe, Bruce T., Diamond, Betty, Wollmuth, Lonnie P.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/51; 14; 14/19; 631/378/1689; 631/378/2586; 631/378/371; 692/4023/1670/1613; 9/30; 9/74; 9/97; Allosteric properties; Animal behavior; Animal memory; Animals; Apoptosis; Autoantibodies; Autoantibodies - immunology; Autoimmune diseases; Cell Death; Central nervous system; Chronic conditions; Disruption; Female; Glutamic acid receptors (ionotropic); Humanities and Social Sciences; Humans; Lupus; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - psychology; Memory tasks; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Modulators; multidisciplinary; N-Methyl-D-aspartic acid receptors; Nervous system; Neuromodulation; Neurons - cytology; Neurons - immunology; Receptors; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - immunology; Science; Science (multidisciplinary); Spatial analysis; Spatial Memory; Systemic lupus erythematosus; Transgenic mice
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15224-w

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. Systemic lupus erythematosus (SLE) is an autoimmune disorder which can have neurological manifestations, including autoantibody targeting of the NMDA receptor. In this study, the authors GluN2A subunit is a target of SLE autoantibodies, using sample derived from patient.