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.
%0 Journal Article
%1 haselmann2018human
%A Haselmann, Holger
%A Mannara, Francesco
%A Werner, Christian
%A Planagumà, Jesús
%A Miguez-Cabello, Federico
%A Schmidl, Lars
%A Grünewald, Benedikt
%A Petit-Pedrol, Mar
%A Kirmse, Knut
%A Classen, Joseph
%A Demir, Fatih
%A Klöcker, Nikolaj
%A Soto, David
%A Doose, Sören
%A Dalmau, Josep
%A Hallermann, Stefan
%A Geis, Christian
%D 2018
%J Neuron
%K doose werner
%N 1
%P 91--105.e9
%R https://doi.org/10.1016/j.neuron.2018.07.048
%T Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction
%U http://www.sciencedirect.com/science/article/pii/S0896627318306469
%V 100
%X 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.
@article{haselmann2018human,
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.},
added-at = {2018-12-18T14:09:47.000+0100},
author = {Haselmann, Holger and Mannara, Francesco and Werner, Christian and Planagumà, Jesús and Miguez-Cabello, Federico and Schmidl, Lars and Grünewald, Benedikt and Petit-Pedrol, Mar and Kirmse, Knut and Classen, Joseph and Demir, Fatih and Klöcker, Nikolaj and Soto, David and Doose, Sören and Dalmau, Josep and Hallermann, Stefan and Geis, Christian},
biburl = {https://www.bibsonomy.org/bibtex/296cefb1b6a0d1c0cf922130451e18550/reichert},
doi = {https://doi.org/10.1016/j.neuron.2018.07.048},
interhash = {0c9ca1b034d9aa7a423af80b7cbba782},
intrahash = {96cefb1b6a0d1c0cf922130451e18550},
issn = {08966273},
journal = {Neuron},
keywords = {doose werner},
number = 1,
pages = {91--105.e9},
timestamp = {2018-12-18T14:09:47.000+0100},
title = {Human Autoantibodies against the AMPA Receptor Subunit GluA2 Induce Receptor Reorganization and Memory Dysfunction},
url = {http://www.sciencedirect.com/science/article/pii/S0896627318306469},
volume = 100,
year = 2018
}