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Abstract:
Circulating autoantibodies (AB) of different immunoglobulin classes (IgM, IgA, and IgG), directed against the obligatory
N-methyl- D -aspartate-receptor subunit NR1 (NMDAR1-AB), belong to the mammalian autoimmune repertoire, and appear
with age-dependently high seroprevalence across health and disease. Upon access to the brain, they can exert NMDAR-
antagonistic/ketamine-like actions. Still unanswered key questions, addressed here, are conditions of NMDAR1-AB
formation/boosting, intraindividual persistence/course in serum over time, and (patho)physiological significance of
NMDAR1-AB in modulating neuropsychiatric phenotypes. We demonstrate in a translational fashion from mouse to human
that (1) serum NMDAR1-AB fluctuate upon long-term observation, independent of blood–brain barrier (BBB) perturbation;
(2) a standardized small brain lesion in juvenile mice leads to increased NMDAR1-AB seroprevalence (IgM + IgG), together
with enhanced Ig-class diversity; (3) CTLA4 (immune-checkpoint) genotypes, previously found associated with autoimmune
disease, predispose to serum NMDAR1-AB in humans; (4) finally, pursuing our prior findings of an early increase in
NMDAR1-AB seroprevalence in human migrants, which implicated chronic life stress as inducer, we independently
replicate these results with prospectively recruited refugee minors. Most importantly, we here provide the first experimental
evidence in mice of chronic life stress promoting serum NMDAR1-AB (IgA). Strikingly, stress-induced depressive-like
behavior in mice and depression/anxiety in humans are reduced in NMDAR1-AB carriers with compromised BBB where
NMDAR1-AB can readily reach the brain. To conclude, NMDAR1-AB may have a role as endogenous NMDAR
antagonists, formed or boosted under various circumstances, ranging from genetic predisposition to, e.g., tumors, infection,
brain injury, and stress, altogether increasing over lifetime, and exerting a spectrum of possible effects, also including
beneficial functions.
