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

Kelvin Chan,Noele Certain,Czeslawa Kowal,Patricio T Huerta,Gabrielle Moody,Betty Diamond,Bruce T Volpe,Tomás S Huerta,Jacquelyn Nestor,Lonnie P Wollmuth

doi:10.1038/s41467-020-15224-w

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.

Highlights

Patients with Systemic lupus erythematosus (SLE) experience various peripheral and central nervous system manifestations including spatial memory impairment
We find that DNRAbs act as positive allosteric modulators (PAMs) at both GluN2A- and GluN2B
To begin to address how these subunits contribute to DNRAb-induced phenotypes, we characterized the effect of a SLE patient-derived monoclonal DNRAb, G11, on heterologously expressed NMDA receptor (NMDAR) composed of human NMDAR subunits, either hGluN1-1a/ hGluN2A or hGluN1-1a/hGluN2B

Summary

Introduction

Patients with Systemic lupus erythematosus (SLE) experience various peripheral and central nervous system manifestations including spatial memory impairment. 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 disease characterized by the presence of autoantibodies directed against multiple self-antigens, including DNA1. These autoantibodies affect multiple organ systems such that SLE patients experience arthritis, renal disease, anemia, rashes, and neuropsychiatric symptoms, including memory disorders and spatial memory impairment[2,3,4]. Non-invasive imaging of SLE patients have revealed hippocampal atrophy and parahippocampal microstructural defects, conferring an advantage to using LPS in disease models[4,18]

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Results

Conclusion