title: Acute mechanisms underlying antibody effects in anti-N-methyl-D-aspartate receptor encephalitis.
abstract: OBJECTIVE
  A severe but treatable form of immune-mediated encephalitis is associated with antibodies in serum and cerebrospinal fluid (CSF) against the GluN1 subunit of the N-methyl-D-aspartate receptor (NMDAR). Prolonged exposure of hippocampal neurons to antibodies from patients with anti-NMDAR encephalitis caused a reversible decrease in the synaptic localization and function of NMDARs. However, acute effects of the antibodies, fate of the internalized receptors, type of neurons affected, and whether neurons develop compensatory homeostatic mechanisms were unknown and are the focus of this study.
  
  
  METHODS
  Dissociated hippocampal neuron cultures and rodent brain sections were used for immunocytochemical, physiological, and molecular studies.
  
  
  RESULTS
  Patient antibodies bind to NMDARs throughout the rodent brain, and decrease NMDAR cluster density in both excitatory and inhibitory hippocampal neurons. They rapidly increase the internalization rate of surface NMDAR clusters, independent of receptor activity. This internalization likely accounts for the observed decrease in NMDAR-mediated currents, as no evidence of direct blockade was detected. Once internalized, antibody-bound NMDARs traffic through both recycling endosomes and lysosomes, similar to pharmacologically induced NMDAR endocytosis. The antibodies are responsible for receptor internalization, as their depletion from CSF abrogates these effects in hippocampal neurons. We find that although anti-NMDAR antibodies do not induce compensatory changes in glutamate receptor gene expression, they cause a decrease in inhibitory synapse density onto excitatory hippocampal neurons.
  
  
  CONCLUSIONS
  Our data support an antibody-mediated mechanism of disease pathogenesis driven by immunoglobulin-induced receptor internalization. Antibody-mediated downregulation of surface NMDARs engages homeostatic synaptic plasticity mechanisms, which may inadvertently contribute to disease progression.
authors.affiliation: Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
authors.forename: Emilia H
authors.initials: EH
authors.lastname: Moscato
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Peng
authors.forename: Ankit
authors.initials: A
authors.lastname: Jain
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Parsons
authors.forename: Josep
authors.initials: J
authors.lastname: Dalmau
authors.forename: Rita J
authors.initials: RJ
authors.lastname: Balice-Gordon
mesh_terms: D000818:Animals; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis / Q000097:blood / Q000276:immunology* / Q000473:pathology*; D001323:Autoantibodies / Q000097:blood* / Q000134:cerebrospinal fluid; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D006624:Hippocampus / Q000276:immunology* / Q000473:pathology; D006801:Humans; D009473:Neuronal Plasticity / Q000276:immunology; D009474:Neurons / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000276:immunology; D013569:Synapses / Q000276:immunology / Q000473:pathology
chemical_list: D001323:Autoantibodies; D016194:Receptors, N-Methyl-D-Aspartate