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

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Sukhvir K Wright, Richard E Rosch, Max A Wilson, Manoj A Upadhya, Divya R Dhangar, Charlie Clarke-Bland, Tamara T Wahid, Sumanta Barman, Norbert Goebels, Jakob Kreye, Harald Prüss, Leslie Jacobson, Danielle S Bassett, Angela Vincent, Stuart D Greenhill, Gavin L Woodhall

Original languageEnglish
Article number1106
Pages (from-to)1106
JournalCommunications Biology
Volume4
Issue number1
DOIs
Published20 Sep 2021

Bibliographical note

Funding Information: We thank Rob Wykes, Jonathan Cornford and Andrea Lieb (University College London, UK) for use of EEG powerband analysis program. We gratefully acknowledge the Children’s Epilepsy Surgery Service at the Birmingham Women’s and Children’s NHS Hospital Trust for human tissue samples as well as the patients and families contributing to the study, and Aston Biomedical Services for laboratory animal care. 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). Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

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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