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

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
Neuron. 2018-10-01; 100(1): 91-105.e9
DOI: 10.1016/j.neuron.2018.07.048

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Haselmann H(1), Mannara F(2), Werner C(3), Planagumà J(2), Miguez-Cabello F(4), Schmidl L(5), Grünewald B(1), Petit-Pedrol M(2), Kirmse K(5), Classen J(6), Demir F(7), Klöcker N(8), Soto D(4), Doose S(9), Dalmau J(10), Hallermann S(11), Geis C(12).

Author information:
(1)Hans-Berger Department of Neurology, Jena University Hospital, Am Klinikum 1,
07747 Jena, Germany; Center for Sepsis Control and Care (CSCC), Jena University
Hospital, Am Klinikum 1, 07747 Jena, Germany.
(2)Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital
Clínic, Universitat de Barcelona, 08036 Barcelona, Spain.
(3)Hans-Berger Department of Neurology, Jena University Hospital, Am Klinikum 1,
07747 Jena, Germany; Department of Biotechnology and Biophysics, Biocenter,
University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
(4)Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital
Clínic, Universitat de Barcelona, 08036 Barcelona, Spain; Laboratori de
Neurofisiologia, Departament de Biomedicina, Facultat de Medicina i Ciències de
la Salut, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona,
Spain.
(5)Hans-Berger Department of Neurology, Jena University Hospital, Am Klinikum 1,
07747 Jena, Germany.
(6)Department of Neurology, University of Leipzig, Liebigstrasse 20, 04103
Leipzig, Germany.
(7)Institute of Neural and Sensory Physiology, Medical Faculty, University of
Düsseldorf, Düsseldorf, Germany; Forschungszentrum Jülich, Central Institute for
Engineering, Electronics and Analytics (ZEA-3), Wilhelm-Johnen-Strasse, 52425
Jülich, Germany.
(8)Institute of Neural and Sensory Physiology, Medical Faculty, University of
Düsseldorf, Düsseldorf, Germany.
(9)Department of Biotechnology and Biophysics, Biocenter, University of Würzburg,
Am Hubland, 97074 Würzburg, Germany.
(10)Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital
Clínic, Universitat de Barcelona, 08036 Barcelona, Spain; Department of
Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA; Institució
Catalana de Recerca i Estudis Avançats (ICREA), Passeig de Lluís Companys, 23,
08010 Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades
Raras (CIBERER), (Instituto Carlos III, Madrid), Av. Monforte de Lemos, 3-5
Pabellón 11, 28029 Madrid, Spain.
(11)Carl-Ludwig-Institute for Physiology, Medical Faculty, University of Leipzig,
Liebigstrasse 27, 04103 Leipzig, Germany.
(12)Hans-Berger Department of Neurology, Jena University Hospital, Am Klinikum 1,
07747 Jena, Germany; Center for Sepsis Control and Care (CSCC), Jena University
Hospital, Am Klinikum 1, 07747 Jena, Germany. Electronic address:
.

Comment in
Nat Rev Neurosci. 2018 Oct;19(10):580-581.

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.

Copyright © 2018 Elsevier Inc. All rights reserved.

 

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