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NMDAR Antibodies Alter Dopamine Receptors and Cause Psychotic Behavior in Mice
Author(s) -
CarcelesCordon Marc,
Mannara Francesco,
Aguilar Esther,
Castellanos Aida,
Planagumà Jesús,
Dalmau Josep
Publication year - 2020
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25829
Subject(s) - dopamine receptor d2 , nmda receptor , dopamine , cerebrospinal fluid , hippocampal formation , prepulse inhibition , medicine , endocrinology , receptor , neuroscience , chemistry , psychology , schizophrenia (object oriented programming) , psychiatry
Objective The aim was to demonstrate that antibodies from patients with anti‐ N ‐methyl‐ d ‐aspartate receptor (NMDAR) encephalitis alter the levels of dopamine 1 receptor (D1R) and dopamine 2 receptor (D2R) and cause psychotic‐like features in mice. Methods Cultured rat hippocampal neurons were treated with cerebrospinal fluid (CSF) from patients with anti‐NMDAR encephalitis or controls, and the effects on clusters of D1R and D2R were quantified. In vivo studies included 71 C57BL/6J mice that were chronically infused with CSF from patients or controls through ventricular catheters connected to subcutaneous osmotic pumps. Prepulse inhibition of the acoustic startling reflex (PPI; a marker of psychotic‐like behavior), memory, locomotor activity, and the density of cell‐surface and synaptic D1R, D2R, and NMDAR clusters were examined at different time points using reported techniques. Results In cultured neurons, CSF from patients, but not from controls, caused a significant decrease of cell‐surface D1R and an increase of D2R clusters. In mice, CSF from patients caused a significant decrease of synaptic and total cell‐surface D1R clusters and an increase of D2R clusters associated with a decrease of PPI. These effects were accompanied by memory impairment and a reduction of surface NMDARs, as reported in this model. The psychotic‐like features, memory impairment, and changes in levels of D1R, D2R, and NMDAR progressively improved several days after the infusion of CSF from patients stopped. Interpretation In addition to memory deficits and reduction of NMDARs, CSF antibodies from patients with anti‐NMDAR encephalitis cause reversible psychotic‐like features accompanied by changes (D1R decrease, D2R increase) in cell‐surface dopamine receptor clusters. ANN NEUROL 2020 ANN NEUROL 2020;88:603–613