Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients

Jézéquel, Julie; Johansson, Emily M.; Dupuis, Julien; Rogemond, Véronique; Gréa, Hélène; Kellermayer, Blanka; Hamdani, Nora; Guen, Emmanuel Le; Rabu, Corentin; Lepleux, Marilyn; Spatola, Marianna; Mathias, Elodie; Bouchet, Delphine; Ramsey, Amy J.; Yolken, Robert H.; Tamouza, Ryad; Dalmau, Josep; Honnorat, Jérôme; Leboyer, Marion; Groc, Laurent

doi:10.1038/s41467-017-01700-3

Cited by 110 publications

(108 citation statements)

References 61 publications

(76 reference statements)

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“…However, in our study, NR1‐IgM rates were surprisingly high in NMDAR‐antibody encephalitis patients and low in disease controls 22. The higher detection rate in the target population may be explained by use of live cell‐based assays, which are known to enhance sensitivity of NR1‐IgG detection 23. Furthermore, perhaps exclusion of intracellular epitope binding explains the low rate observed in disease controls.…”

Section: Discussioncontrasting

confidence: 56%

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

Makuch

Wilson

Al-Diwani

et al. 2018

Annals of Neurology

102

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IntroductionN‐methyl‐D‐aspartate receptor (NMDAR) antibody encephalitis is mediated by immunoglobulin G (IgG) autoantibodies directed against the NR1 subunit of the NMDAR. Around 20% of patients have an underlying ovarian teratoma, and the condition responds to early immunotherapies and ovarian teratoma removal. However, despite clear therapeutic relevance, mechanisms of NR1‐IgG production and the contribution of germinal center B cells to NR1‐IgG levels are unknown.MethodsClinical data and longitudinal paired serum NR1‐reactive IgM and IgG levels from 10 patients with NMDAR‐antibody encephalitis were determined. Peripheral blood mononuclear cells from these 10 patients, and two available ovarian teratomas, were stimulated with combinations of immune factors and tested for secretion of total IgG and NR1‐specific antibodies.ResultsIn addition to disease‐defining NR1‐IgG, serum NR1‐IgM was found in 6 of 10 patients. NR1‐IgM levels were typically highest around disease onset and detected for several months into the disease course. Moreover, circulating patient B cells were differentiated into CD19+CD27++CD38++ antibody‐secreting cells in vitro and, from 90% of patients, secreted NR1‐IgM and NR1‐IgG. Secreted levels of NR1‐IgG correlated with serum NR1‐IgG (p < 0.0001), and this was observed across the varying disease durations, suggestive of an ongoing process. Furthermore, ovarian teratoma tissue contained infiltrating lymphocytes which produced NR1‐IgG in culture.InterpretationSerum NR1‐IgM and NR1‐IgG, alongside the consistent production of NR1‐IgG from circulating B cells and from ovarian teratomas suggest that ongoing germinal center reactions may account for the peripheral cell populations which secrete NR1‐IgG. Cells participating in germinal center reactions might be a therapeutic target for the treatment of NMDAR‐antibody encephalitis. Ann Neurol 2018;83:553–561

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Section: Discussioncontrasting

confidence: 56%

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

Makuch

Wilson

Al-Diwani

et al. 2018

Annals of Neurology

102

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“…NMDAR encephalitis causes internalisation of the NMDAR, resulting in a reversible reduction in the number of receptors and impaired αamino3hydroxy5methyl4isoxazolepropionic acid (AMPA) receptormediated longterm potentiation. 121,122 This idea is consistent with catatonia also resulting from use of the recreational noncompetitive NMDAR antagonists, ketamine, and phencyclidine. 117,123 To integrate findings of effective treatment with GABAA receptor agonists and NMDAR antagonists, Northoff 66 has proposed a model of catatonia in which the normal inhibition of excitatory glutamatergic cortico cortical association fibres by GABAergic neurons in the orbitofrontal region is impaired.…”

Section: A Model For Glutamatergic Hypofunction In Catatoniasupporting

confidence: 54%

Catatonia and the immune system: a review

Rogers

Pollak

Blackman

et al. 2019

The Lancet Psychiatry

138

117

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Catatonia is a psychomotor disorder featuring stupor, posturing, and echophenomena. This Series paper examines the evidence for immune dysregulation in catatonia. Activation of the innate immune system is associated with mutism, withdrawal, and psychomotor retardation, which constitute the neurovegetative features of catatonia. Evidence is sparse and conflicting for acute-phase activation in catatonia, and whether this feature is secondary to immobility is unclear. Various viral, bacterial, and parasitic infections have been associated with catatonia, but it is primarily linked to CNS infections. The most common cause of autoimmune catatonia is N-methyl-D-aspartate receptor (NMDAR) encephalitis, which can account for the full spectrum of catatonic features. Autoimmunity appears to cause catatonia less by systemic inflammation than by the downstream effects of specific actions on extracellular antigens. The specific association with NMDAR encephalitis supports a hypothesis of glutamatergic hypofunction in catatonia.

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“…Our work here does not discount the possibility that DNRAbs act on additional mechanisms, independent of NMDAR gating, to exert their subunit-specific effects. The pathology of anti-NMDAR encephalitis, for example, largely does not involve receptor gating, but rather changes in cell biology: autoantibodies cause internalization of NMDARs and chronic NMDAR hypofunction 57,58 , displace the interaction of NMDAR with synaptic proteins such as the EphrinB2 receptor 59,60 or disrupt the nanoscale organization of NMDARs at the synapse with subunit-selectivity 61 . DNRAbs may also engage different intracellular pathways associated with GluN2A and GluN2B.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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

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Dynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients

Cited by 110 publications

References 61 publications

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

Catatonia and the immune system: a review

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

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