Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction

Neuron. 2018 Oct 10;100(1):91-105.e9. doi: 10.1016/j.neuron.2018.07.048. Epub 2018 Aug 23.


AMPA receptors are essential for fast excitatory transmission in the CNS. Autoantibodies to AMPA receptors have been identified in humans with autoimmune encephalitis and severe defects of hippocampal function. Here, combining electrophysiology and high-resolution imaging with neuronal culture preparations and passive-transfer models in wild-type and GluA1-knockout mice, we analyze how specific human autoantibodies against the AMPA receptor subunit GluA2 affect receptor function and composition, synaptic transmission, and plasticity. Anti-GluA2 antibodies induce receptor internalization and a reduction of synaptic GluA2-containing AMPARs followed by compensatory ryanodine receptor-dependent incorporation of synaptic non-GluA2 AMPARs. Furthermore, application of human pathogenic anti-GluA2 antibodies to mice impairs long-term synaptic plasticity in vitro and affects learning and memory in vivo. Our results identify a specific immune-neuronal rearrangement of AMPA receptor subunits, providing a framework to explain disease symptoms.

Keywords: AMPA receptor; GluA2 subunit; TARP; autoantibody; autoimmune encephalitis; dSTORM; passive-transfer; super-resolution microscopy; synaptic plasticity; synaptic scaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies / immunology
  • Autoantibodies / pharmacology*
  • Autoantigens / immunology
  • Encephalitis / complications
  • Encephalitis / immunology
  • Encephalitis / physiopathology*
  • Hashimoto Disease / complications
  • Hashimoto Disease / immunology
  • Hashimoto Disease / physiopathology*
  • Hippocampus / drug effects
  • Humans
  • Memory Disorders / etiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuronal Plasticity / drug effects*
  • Neurons / drug effects
  • Receptors, AMPA / drug effects*
  • Receptors, AMPA / immunology
  • Synaptic Transmission / drug effects*


  • Autoantibodies
  • Autoantigens
  • Receptors, AMPA
  • glutamate receptor ionotropic, AMPA 2

Supplementary concepts

  • Hashimoto's encephalitis