Background/Purpose: 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). The underlying subunit specificity for DNRAbs to mediate SLE neuropathological effects are currently unknown. Here, we characterize the specific subunit effects of DNRAbs on NMDA receptors.

Methods: We employ whole-cell and single-channel patch clamp electrophysiology to study the mechanism of potentiating NMDAR currents by DNRAbs. We employ primary neuronal cell cultures, pharmacology, and ICC to test for subunit-specific NMDAR antagonists to block DNRAb-mediated cell death. We employ transgenic animals to selectively knock out NMDAR subunits for immunohistochemistry, microglia assessment, in vivo place field recordings, and spatial memory behavior testing.

Results: 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. Finally, spatial memory defects resulting from aberrant hippocampal place fields affected by DNRAbs require GluN2A-containing NMDARs as well.

Conclusion: Our results indicate that GluN2A is the primary subunit that drives DNRAb-mediated NMDAR potentiation, and SLE cognitive/spatial memory defects. Thus, GluN2A-specific antagonists or negative allosteric modulators are strong candidates to treat SLE patients with nervous system dysfunction.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lupus-auto-antibodies-act-as-positive-allosteric-modulators-at-glun2a-containing-nmda-receptors-to-induce-excitotoxicity-and-spatial-memory-deficits/