Patients with systemic lupus erythematosus (SLE) experience cognitive abnormalities in multiple domains including processing speed, executive function, and memory. Here we show that SLE patients carrying antibodies that bind DNA and the GluN2A and GluN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), termed DNRAbs, displayed a selective impairment in spatial recall. Neural recordings in a mouse model of SLE, in which circulating DNRAbs penetrate the hippocampus, revealed that CA1 place cells exhibited a significant expansion in place field size. Structural analysis showed that hippocampal pyramidal cells had substantial reductions in their dendritic processes and spines. Strikingly, these abnormalities became evident at a time when DNRAbs were no longer detectable in the hippocampus. These results suggest that antibody-mediated neurocognitive impairments may be highly specific, and that spatial cognition may be particularly vulnerable to DNRAb-mediated structural and functional injury to hippocampal cells that evolves after the triggering insult is no longer present.
Keywords: AP, alkaline phosphatase; BBB, blood–brain barrier; BDI, Beck depression index; C3, C4, complements 3 and 4, respectively; CA1 place cell; CA1, cornus ammonis area 1 of the hippocampus; CNS, central nervous system; CSF, cerebrospinal fluid; DMARD, disease-modifying drugs; DNRAb, anti-DNA antibody reactive to the GluN2A and GluN2B subunits of the NMDAR; DWEYS, amino acid consensus sequence (D/E, W, D/E, Y, S/G) for DNRAb binding; FA, Freund's adjuvant; HC, healthy control; HEK-293T, human embryonic kidney 293 T cell; Hippocampus; IgG, immunoglobulin G; LPS, lipopolysaccharide; Lupus; MAP, multi-antigenic polylysine backbone; Mouse lupus model; NMDAR, N-methyl-d-aspartate receptor; NOR, novel object recognition; NPSLE, neuropsychiatric lupus; Neuropsychiatric lupus; OPM, object place memory; SELENA, safety of estrogens in lupus erythematosus national assessment; SLE, systemic lupus erythematosus; SLEDAI, systemic lupus erythematosus disease activity index; SLICCDI, systemic lupus international collaborating clinics damage index; dsDNA, double stranded DNA; i.p, intraperitoneally.