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

Abstract

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.

• Authors: Holger Haselmann, Francesco Mannara, Christian Werner, Jesús Planagumà, Federico Miguez-Cabello, Lars Schmidl, Benedikt Grünewald, Mar Petit-Pedrol, Knut Kirmse, Joseph Classen, Fatih Demir, Nikolaj Klöcker, David Soto, Sören Doose, Josep Dalmau, Stefan Hallermann, Christian Geis
• Journal: Neuron (Neuron) Vol. 100 Issue 1 Pg. 91-105.e9 (10 10 2018) ISSN: 1097-4199 [Electronic] United States
• PMID: 30146304 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• Animals
• Autoantibodies (immunology, pharmacology)
• Autoantigens (immunology)
• Encephalitis (complications, immunology, physiopathology)
• Hashimoto Disease (complications, immunology, 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, immunology)
• Synaptic Transmission (drug effects)