Effects of sustained i.c.v. infusion of lupus CSF and autoantibodies on behavioral phenotype and neuronal calcium signaling

Abstract

Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease that is often accompanied by brain atrophy and diverse neuropsychiatric manifestations of unknown origin. More recently, it was observed that cerebrospinal fluid (CSF) from patients and lupus-prone mice can be neurotoxic and that acute administration of specific brain-reactive autoantibodies (BRAs) can induce deficits in isolated behavioral tasks. Given the chronic and complex nature of CNS SLE, the current study examines broad behavioral performance and neuronal Ca2+ signaling in mice receiving a sustained infusion of cerebrospinal fluid (CSF) from CNS SLE patients and putative BRAs (anti-NR2A, anti-ribosomal P, and anti-α-tubulin). A 2-week intracerebroventricular (i.c.v.) infusion of CSF altered home-cage behavior and induced olfactory dysfunction, excessive immobility in the forced swim test, and perseveration in a learning task. Conversely, sustained administration of purified BRAs produced relatively mild, both inhibitory and stimulatory effects on olfaction, spatial learning/memory, and home-cage behavior. In vitro studies revealed that administration of some CSF samples induces a rapid influx of extracellular Ca2+ into murine neurons, an effect that could be partially mimicked with the commercial anti-NR2A antibody and blocked with selective N-methyl-D-aspartate (NMDA) receptor antagonists. The current findings confirm that the CSF from CNS SLE patients can be neuroactive and support the hypothesis that intrathecal BRAs induce synergistically diverse effects on all domains of behavior. In addition, anti-NMDA receptor antibodies may alter Ca2+ homeostasis of central neurons, thus accounting for excitotoxicity and contributing to the heterogeneity of psychiatric manifestations in CNS SLE and other autoantibody-related brain disorders.Electronic supplementary materialThe online version of this article (10.1186/s40478-017-0473-1) contains supplementary material, which is available to authorized users.

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

“…Hence, we assume that the PAM action is a common feature of all DNRAbs. Consistent with this idea, polyclonal antibodies from the CSF of SLE patient with neuropsychiatric symptoms that bind the DWEYS motif induce NMDAR hyperfunction 12,33 . Nevertheless, it is possible that there are clonal variations in the magnitude of the PAM action as well as possible additional functional effects of DNRAbs, necessitating the study of more SLE patient DNRAbs.…”

“…The prevalence of diffuse nervous system disorders is reported from 20-90%, depending on the particular functional assessment [5][6][7] . These cognitive defects in both clinical and pre-clinical conditions are often associated with DNRAb, anti-double-stranded DNA (dsDNA) antibodies with cross-reactivity to NMDA receptors (NMDAR) [8][9][10][11][12][13][14] .…”

Differential Effects of Chronic Immunosuppression on Behavioral, Epigenetic and Alzheimer’s Disease-Associated Markers in 3xTg-AD Mice

“…In each block, mice were exposed to tests re ective of neurological/sensorimotor function, spontaneous locomotor activity and emotional reactivity. These tests were performed during the dark phase in the following order: basic re exes, beam walking, Rotarod, olfactory sensitivity, T-maze alternation, novel object, open eld, step-down, Morris water maze, and spontaneous activity, as described earlier in detail [52,65,95].…”

Differential Effects of Chronic Immunosuppression on Behavioral, Epigenetic and Alzheimer’s Disease-Associated Markers in 3xtg-AD Mice 

“…In each block, mice were exposed to tests re ective of neurological/sensorimotor function, spontaneous locomotor activity and emotional reactivity. These tests were performed during the dark phase in the following order: basic re exes, beam walking, Rotarod, olfactory sensitivity, T-maze alternation, novel object, open eld, step-down, Morris water maze, and spontaneous activity, as described earlier in detail [55,69,100].…”

“…Summary of behavioral data collected. Descriptions of methodology and variables tested are described in detail in previous reports[55,69,100].…”