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

Abstract

The identification of circulating autoantibodies against neuronal receptors in neuropsychiatric disorders has fostered new conceptual and clinical frameworks. However, detection reliability, putative presence in different diseases and in health have raised questions about potential pathogenic mechanism mediated by autoantibodies. Using a combination of single molecule-based imaging approaches, we here ascertain the presence of circulating autoantibodies against glutamate NMDA receptor (NMDAR-Ab) in about 20% of psychotic patients diagnosed with schizophrenia and very few healthy subjects. NMDAR-Ab from patients and healthy subjects do not compete for binding on native receptor. Strikingly, NMDAR-Ab from patients, but not from healthy subjects, specifically alter the surface dynamics and nanoscale organization of synaptic NMDAR and its anchoring partner the EphrinB2 receptor in heterologous cells, cultured neurons and in mouse brain. Functionally, only patients’ NMDAR-Ab prevent long-term potentiation at glutamatergic synapses, while leaving NMDAR-mediated calcium influx intact. We unveil that NMDAR-Ab from psychotic patients alter NMDAR synaptic transmission, supporting a pathogenically relevant role.

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

“…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.…”

Catatonia and the immune system: a review

“…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.…”

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

“…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.…”