Multimodal electrophysiological analyses reveal that reduced synaptic excitatory neurotransmission underlies seizures in a model of NMDAR antibody-mediated encephalitis


Seizures are a prominent feature in N-Methyl-D-Aspartate receptor antibody (NMDAR antibody) encephalitis, a distinct neuro-immunological disorder in which specific human autoantibodies bind and crosslink the surface of NMDAR proteins thereby causing internalization and a state of NMDAR hypofunction. To further understand ictogenesis in this disorder, and to test a potential treatment compound, we developed an NMDAR antibody mediated rat seizure model that displays spontaneous epileptiform activity in vivo and in vitro. Using a combination of electrophysiological and dynamic causal modelling techniques we show that, contrary to expectation, reduction of synaptic excitatory, but not inhibitory, neurotransmission underlies the ictal events through alterations in the dynamical behaviour of microcircuits in brain tissue. Moreover, in vitro application of a neurosteroid, pregnenolone sulphate, that upregulates NMDARs, reduced established ictal activity. This proof-of-concept study highlights the complexity of circuit disturbances that may lead to seizures and the potential use of receptor-specific treatments in antibody-mediated seizures and epilepsy.

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Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences > Aston Institute of Health & Neurodevelopment (AIHN)
College of Health & Life Sciences
College of Health & Life Sciences > Clinical and Systems Neuroscience
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit Funding: S.K.W. was funded by an Epilepsy Research UK Fellowship (F3001) and Wellcome Trust Clinical Research Career Development Fellowship (216613/Z/19/Z) during this work. H.P. received support from the German Research Foundation (DFG; grant numbers PR1274/3-1, 4-1, 5-1) and the German Federal Ministry of Education and Research (BMBF; Connect-Generate). N.G. received support from the German Ministry for Education and Research (BMBF; 31P7398 and Connect-Generate), the National Multiple Sclerosis Society (NMSS; BRAVEinMS), the Wellcome Trust (208938/Z/17/Z) and the Forschungskommission of the Medical Faculty of the Heinrich-Heine-University. S.D.G. and D.D. funded in part by the Academy of Medical Sciences (SBF004\1053).
Uncontrolled Keywords: Medicine (miscellaneous),Biochemistry, Genetics and Molecular Biology(all),Agricultural and Biological Sciences(all)
Publication ISSN: 2399-3642
Last Modified: 23 Apr 2024 07:24
Date Deposited: 27 Sep 2021 10:52
Full Text Link:
Related URLs: https://www.nat ... 003-021-02635-8 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2021-09-20
Accepted Date: 2021-09-02
Authors: Wright, Sukhvir K (ORCID Profile 0000-0002-5464-3779)
Rosch, Richard E
Wilson, Max A
Upadhya, Manoj A (ORCID Profile 0000-0002-2032-1472)
Dhangar, Divya R (ORCID Profile 0000-0002-0363-627X)
Clarke-Bland, Charlie
Wahid, Tamara T
Barman, Sumanta
Goebels, Norbert
Kreye, Jakob
Prüss, Harald
Jacobson, Leslie
Bassett, Danielle S
Vincent, Angela
Greenhill, Stuart D (ORCID Profile 0000-0002-5038-5258)
Woodhall, Gavin L (ORCID Profile 0000-0003-1281-9008)



Version: Published Version

License: Creative Commons Attribution

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