Selective Impairment of Spatial Cognition Caused by Autoantibodies to the N-Methyl-D-Aspartate Receptor.
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.
Laboratory of Immune & Neural Networks, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA.
Eric H
EH
Chang
Laboratory of Functional Neuroanatomy, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA ; Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY 11030, USA.
Bruce T
BT
Volpe
Autoimmune & Musculoskeletal Disease Center, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA.
Meggan
M
Mackay
Autoimmune & Musculoskeletal Disease Center, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA.
Cynthia
C
Aranow
Department of Psychology, Queens College, Flushing, NY 11367, USA.
Philip
P
Watson
Autoimmune & Musculoskeletal Disease Center, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA.
Czeslawa
C
Kowal
Department of Psychology, Queens College, Flushing, NY 11367, USA.
Justin
J
Storbeck
Susan and Leonard Feinstein Center for Neurosciences, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA.
Paul
P
Mattis
Laboratory of Functional Neuroanatomy, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA.
RoseAnn
R
Berlin
School of Biological Sciences, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637551, Singapore.
Huiyi
H
Chen
Autoimmune & Musculoskeletal Disease Center, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA.
Simone
S
Mader
Laboratory of Immune & Neural Networks, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA.
Tomás S
TS
Huerta
Laboratory of Immune & Neural Networks, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA ; Autoimmune & Musculoskeletal Disease Center, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA ; Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY 11030, USA.
Patricio T
PT
Huerta
Autoimmune & Musculoskeletal Disease Center, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA ; Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY 11030, USA.
Betty
B
Diamond
D000328:Adult; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D001323:Autoantibodies / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003071:Cognition; D003712:Dendrites / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008297:Male; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D017966:Pyramidal Cells / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology*; D013028:Space Perception; D065852:Spatial Memory
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D016194:Receptors, N-Methyl-D-Aspartate
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