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.
Highlights
The identification of circulating autoantibodies against neuronal receptors in neuropsychiatric disorders has fostered new conceptual and clinical frameworks
We show that circulating Nmethyl-D-aspartate receptors (NMDAR)-Ab are detected in about 20% of psychotic patients diagnosed with SCZ and only in very few healthy subjects
As NMDAR-Ab bind extracellular epitope(s) of the receptor and can perturb interactions between NMDAR and an anchoring partner, we primarily focused our attention on the EphrinB2 receptor (EphB2R), as it strongly retains synaptic NMDAR through a direct interaction of their respective extracellular domains[50]
Summary
The identification of circulating autoantibodies against neuronal receptors in neuropsychiatric disorders has fostered new conceptual and clinical frameworks. 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. Autoantibodies against neuronal receptors have been increasingly identified in neuropsychiatric disorders[1,2,3,4,5,6] These disease-related autoantibodies had generated excitement towards molecular and cellular dissection of psychiatric disorders and has fostered debate on how to identify the patients that may benefit from immunotherapy[7]. NMDAR-Ab from patients, but not from healthy subjects, alter the surface dynamics and nanoscale organization of synaptic NMDAR, preventing long-term potentiation (LTP) at glutamatergic synapses
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