Journal article
Peripherally-derived LGI1-reactive monoclonal antibodies cause epileptic seizures in vivo
- Abstract:
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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-monoclonal antibodies (mAbs)], derived from patient circulating B cells. These were directed towards both major domains of LGI1, leucine-rich repeat and epitempin repeat, 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 status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 564.2KB, Terms of use)
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- Publisher copy:
- 10.1093/brain/awae129
Authors
- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 104079/Z/14/Z
- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MR/V007173/1
- Publisher:
- Oxford University Press
- Journal:
- Brain More from this journal
- Volume:
- 147
- Issue:
- 8
- Pages:
- 2636-2642
- Publication date:
- 2024-04-25
- Acceptance date:
- 2024-04-05
- DOI:
- EISSN:
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1460-2156
- ISSN:
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0006-8950
- Pmid:
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38662480
- Language:
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English
- Keywords:
- Pubs id:
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1992304
- Local pid:
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pubs:1992304
- Deposit date:
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2025-02-05
- ARK identifier:
Terms of use
- Copyright holder:
- Upadhya et al.
- Copyright date:
- 2024
- Rights statement:
- © 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.
- Licence:
- CC Attribution (CC BY)
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