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@ARTICLE{vanCasteren:165620,
author = {van Casteren, Adriana C M and Ackermann, Frauke and Rahman,
Kazi Atikur and Andrzejak, Ewa and Rosenmund, Christian and
Kreye, Jakob and Prüss, Harald and Garner, Craig Curtis and
Ichkova, Aleksandra},
title = {{D}ifferential modes of action of α1- and α1γ2-
autoantibodies derived from patients with {GABAAR}
encephalitis.},
journal = {eNeuro},
volume = {9},
number = {6},
issn = {2373-2822},
address = {Washington, DC},
publisher = {Soc.},
reportid = {DZNE-2022-01753},
pages = {ENEURO.0369-22.2022},
year = {2022},
abstract = {Autoantibodies against central nervous system proteins are
increasingly being recognized in association with neurologic
disorders. Although a growing number of neural
autoantibodies have been identified, a causal link between
specific autoantibodies and disease symptoms remains
unclear, as most studies use patient-derived CSF-containing
mixtures of autoantibodies. This raises questions concerning
mechanism of action and which autoantibodies truly
contribute to disease progression. To address this issue,
monoclonal autoantibodies were isolated from a young girl
with a range of neurologic symptoms, some of which reacted
with specific GABAA receptor (GABAAR) subunits, α1-subunit
and α1γ2-subunit, which in this study we have
characterized in detail using a combination of cellular
imaging and electrophysiological techniques. These studies
in neurons from wild-type mice (C57BL/6J;
$RRID:IMSR_JAX:000664)$ of mixed-sex revealed that the α1
and α1γ2 subunit-specific antibodies have differential
effects on the GABAA receptor. Namely, the α1-antibody was
found to directly affect GABAA receptor function on a short
time scale that diminished GABA currents, leading to
increased network excitability. On longer time scales those
antibodies also triggered a redistribution of the GABAA
receptor away from synapses. In contrast, the
α1γ2-antibody had no direct effect on GABAA receptor
function and could possibly mediate its effect through other
actors of the immune system. Taken together, these data
highlight the complexity underlying autoimmune disorders and
show that antibodies can exert their effect through many
mechanisms within the same disease.},
keywords = {Animals / Mice / Receptors, GABA-A: metabolism /
Autoantibodies: metabolism / Mice, Inbred C57BL /
Encephalitis / gamma-Aminobutyric Acid / Receptors, GABA-A
(NLM Chemicals) / GABAAR (Other) / autoantibodies (Other) /
autoimmune encephalitis (Other) / cortical/striatal neurons
(Other) / network excitability (Other) / Autoantibodies (NLM
Chemicals) / gamma-Aminobutyric Acid (NLM Chemicals)},
cin = {AG Garner / AG Prüß / AG Ackermann},
ddc = {610},
cid = {I:(DE-2719)1810001 / I:(DE-2719)1810003 /
I:(DE-2719)1813004},
pnm = {351 - Brain Function (POF4-351) / 353 - Clinical and Health
Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-351 / G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pmc = {pmc:PMC9765394},
pubmed = {pmid:36446572},
doi = {10.1523/ENEURO.0369-22.2022},
url = {https://pub.dzne.de/record/165620},
}