Peripherally-derived LGI1-reactive monoclonal antibodies cause epileptic seizures in vivo

Abstract

One striking clinical hallmark in patients with autoantibodies to leucine-rich glioma inactivated 1 (LGI1) is the very frequent focal seizure semiologies, including faciobrachial dystonic seizures (FBDS), in addition to the amnesia. Polyclonal serum IgGs have successfully modelled the cognitive changes in vivo but not seizures. Hence, it remains unclear whether LGI1-autoantibodies are sufficient to cause seizures. We tested this with the molecularly precise monoclonal antibodies directed against LGI1 (LGI1-mAbs), derived from patient circulating B cells. These were directed towards both major domains of LGI1, LRR and EPTP and infused intracerebroventricularly over 7 days into juvenile male Wistar rats using osmotic pumps. Continuous wireless EEG was recorded from a depth electrode placed in hippocampal CA3 plus behavioural tests for memory and hyperexcitability were performed. Following infusion completion (Day 9), post-mortem brain slices were studied for antibody binding and effects on Kv1.1. The LGI1-mAbs bound most strongly in the hippocampal CA3 region and induced a significant reduction in Kv1.1 cluster number in this subfield. By comparison to control-Ab injected rats video-EEG analysis over 9 days revealed convulsive and non-convulsive seizure activity in rats infused with LGI1-mAbs, with a significant number of ictal events. Memory was not impaired in the novel object recognition test. Peripherally-derived human LGI1-mAbs infused into rodent CSF provide strong evidence of direct in vivo epileptogenesis with molecular correlations. These findings fulfill criteria for LGI1-antibodies in seizure causation.

Publication DOI: https://doi.org/10.1093/brain/awae129
Divisions: College of Health & Life Sciences > Aston Pharmacy School
Funding Information: This was supported by a Wellcome Trust Fellowship [216613/Z/19/Z] to S.K.W; a senior clinical fellowship from the Medical Research Council [MR/V007173/1] and Wellcome Trust Fellowship [104079/Z/14/Z] to S.R.I., the German Research Foundation [FOR3004 SYNA
Additional Information: Copyright © The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Publication ISSN: 1460-2156
Data Access Statement: Data are available on request
Last Modified: 20 May 2024 07:45
Date Deposited: 08 May 2024 14:33
Full Text Link:
Related URLs: https://academi ... awae129/7658324 (Publisher URL)
PURE Output Type: Article
Published Date: 2024-04-25
Published Online Date: 2024-04-25
Accepted Date: 2024-04-23
Authors: Upadhya, Manoj (ORCID Profile 0000-0002-2032-1472)
Kirmann, Toni
Wilson, Max A.
Simon, Christian M.
Dhangar, Divya (ORCID Profile 0000-0002-0363-627X)
Geis, Christian
Williams, Robyn
Woodhall, Gavin (ORCID Profile 0000-0003-1281-9008)
Hallermann, Stefan
Irani, Sarosh R.
Wright, Sukhvir K. (ORCID Profile 0000-0002-5464-3779)

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