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

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 GluN2Acontaining NMDARs. Our results indicate that GluN2A-specific antagonists or negative allosteric modulators are strong candidates to treat SLE patients with nervous system dysfunction.

Positive allosteric modulation of NMDA receptors: mechanisms, physiological impact and therapeutic potential

“…GluN2B-NMDARs are thus a target worth investigating for positive allosteric modulation. In fact, GluN2A-NMDAR overactivation can also be toxic (Hardingham & Bading, 2010;Papouin & Oliet, 2014;Chan et al 2020; and see above). It thus seems that the parameters setting the cursor between pro-survival and pro-toxicity might go beyond the NMDAR subtype and subcellular expression.…”

“…A subset of autoantibodies from patients suffering from systemic lupus erythrematosus (SLE) act as GluN2A-specific PAMs (Chan et al 2020;Wollmuth et al 2021). In that case enhancing GluN2A-NMDARs is clearly deleterious.…”

“…Indeed, mice immunized with these antibodies display increased neuronal death, dendritic pruning and impaired spatial memory (reviewed in Wollmuth et al 2021). This effect is dependent on the GluN2A subunit, since GluN2A-KO mice are protected against the deleterious effects of SLE autoantibodies (Chan et al 2020). This highlights the potential narrow therapeutic window of a selective boost of GluN2A-NMDAR activity.…”