title: Cellular plasticity induced by anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis antibodies.
abstract: OBJECTIVE
  Autoimmune-mediated anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis is a severe but treatment-responsive disorder with prominent short-term memory loss and seizures. The mechanisms by which patient antibodies affect synapses and neurons leading to symptoms are poorly understood.
  
  
  METHODS
  The effects of patient antibodies on cultures of live rat hippocampal neurons were determined with immunostaining, Western blot, and electrophysiological analyses.
  
  
  RESULTS
  We show that patient antibodies cause a selective decrease in the total surface amount and synaptic localization of GluA1- and GluA2-containing AMPARs, regardless of receptor subunit binding specificity, through increased internalization and degradation of surface AMPAR clusters. In contrast, patient antibodies do not alter the density of excitatory synapses, N-methyl-D-aspartate receptor (NMDAR) clusters, or cell viability. Commercially available AMPAR antibodies directed against extracellular epitopes do not result in a loss of surface and synaptic receptor clusters, suggesting specific effects of patient antibodies. Whole-cell patch clamp recordings of spontaneous miniature postsynaptic currents show that patient antibodies decrease AMPAR-mediated currents, but not NMDAR-mediated currents. Interestingly, several functional properties of neurons are also altered: inhibitory synaptic currents and vesicular γ-aminobutyric acid transporter (vGAT) staining intensity decrease, whereas the intrinsic excitability of neurons and short-interval firing increase.
  
  
  CONCLUSIONS
  These results establish that antibodies from patients with anti-AMPAR encephalitis selectively eliminate surface and synaptic AMPARs, resulting in a homeostatic decrease in inhibitory synaptic transmission and increased intrinsic excitability, which may contribute to the memory deficits and epilepsy that are prominent in patients with this disorder.
authors.affiliation: Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Peng
authors.forename: Ethan G
authors.initials: EG
authors.lastname: Hughes
authors.forename: Emilia H
authors.initials: EH
authors.lastname: Moscato
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; D000906:Antibodies / Q000378:metabolism*; D002478:Cells, Cultured; D004660:Encephalitis / Q000276:immunology*; D005260:Female; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008875:Middle Aged; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D000906:Antibodies; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C104722:glutamate receptor ionotropic, AMPA 2