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Patient-derived monoclonal LGI1 autoantibodies elicit seizures, behavioral changes and brain MRI abnormalities in rodent models

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Title: Patient-derived monoclonal LGI1 autoantibodies elicit seizures, behavioral changes and brain MRI abnormalities in rodent models
Authors: Manoj Upadhya, Alexander Stumpf, Jack O’Brien-Cairney, César Cordero Gómez, Jan Döring, Julius Hoffmann, Susanne Mueller, Yuko Fukata, Scott van Hoof, Divya Dhangar, Max A. Wilson, Arunvir Atwal, Richard Rosch, Gavin Woodhall, Philipp Boehm-Sturm, Masaki Fukata, Jakob Kreye, Dietmar Schmitz, Sukhvir K. Wright, Hans-Christian Kornau, Harald Prüss
Source: Brain, behavior and immunity 126, 342-355 (2025). doi:10.1016/j.bbi.2025.02.019
Publisher Information: Elsevier BV, 2025.
Publication Year: 2025
Subject Terms: Male, Behavior, Animal, Intracellular Signaling Peptides and Proteins, Antibodies, Monoclonal, Brain, Proteins, Human monoclonal antibody, Seizure, Magnetic Resonance Imaging, Hippocampus, Rats, Mice, Inbred C57BL, Mice, Disease Models, Animal, ddc:150, Seizures, Limbic Encephalitis, Animals, Humans, Animal model, LGI1, Female, Limbic encephalitis, Autoantibodies
Description: Limbic encephalitis with leucine-rich glioma inactivated 1 (LGI1) protein autoantibodies is associated with cognitive impairment, psychiatric symptoms, and seizures, including faciobrachial dystonic seizures (FBDS). Patient-derived LGI1-autoantibodies cause isolated symptoms of memory deficits in mice and seizures in rats. Using a multimodal experimental approach, we set out to improve the validity of existing in vivo rodent models to further recapitulate the full clinical syndrome of anti-LGI1 antibody mediated disease.A monoclonal anti-LGI1 antibody (anti-LGI1 mAb) derived from a patient's CSF antibody-secreting cell was infused intracerebroventricularly (ICV) into rats and mice for one or two weeks, respectively. Cellular excitability of CA3 pyramidal neurons was determined in hippocampal slices. Structural changes in mouse brains were explored using MRI. Antibody effects on behavior and brain activity of rats were studied using video-EEG.Anti-LGI1 mAbs augmented the excitability of CA3 pyramidal neurons and elicited convulsive and non-convulsive spontaneous epileptic seizures in mice and rats. Mice displayed a hypoactive and anxious phenotype during behavioral testing. MRI revealed acutely increased hippocampal volume after ICV anti-LGI1 mAb infusion. Video-EEG recordings of juvenile rats uncovered two peaks of seizure frequency during the 7-day antibody infusion period resembling the natural progression of seizures in human anti-LGI1 encephalitis.Our data strongly corroborate and extend our understanding of the direct pathogenic and epileptogenic role of human LGI1 autoantibodies.
Document Type: Article
Language: English
ISSN: 0889-1591
DOI: 10.1016/j.bbi.2025.02.019
Access URL: https://pubmed.ncbi.nlm.nih.gov/39984135
https://pub.dzne.de/record/277509
Rights: CC BY
Accession Number: edsair.doi.dedup.....122ea68d6d3dabebd7b76401694e71b9
Database: OpenAIRE
Description
Abstract:Limbic encephalitis with leucine-rich glioma inactivated 1 (LGI1) protein autoantibodies is associated with cognitive impairment, psychiatric symptoms, and seizures, including faciobrachial dystonic seizures (FBDS). Patient-derived LGI1-autoantibodies cause isolated symptoms of memory deficits in mice and seizures in rats. Using a multimodal experimental approach, we set out to improve the validity of existing in vivo rodent models to further recapitulate the full clinical syndrome of anti-LGI1 antibody mediated disease.A monoclonal anti-LGI1 antibody (anti-LGI1 mAb) derived from a patient's CSF antibody-secreting cell was infused intracerebroventricularly (ICV) into rats and mice for one or two weeks, respectively. Cellular excitability of CA3 pyramidal neurons was determined in hippocampal slices. Structural changes in mouse brains were explored using MRI. Antibody effects on behavior and brain activity of rats were studied using video-EEG.Anti-LGI1 mAbs augmented the excitability of CA3 pyramidal neurons and elicited convulsive and non-convulsive spontaneous epileptic seizures in mice and rats. Mice displayed a hypoactive and anxious phenotype during behavioral testing. MRI revealed acutely increased hippocampal volume after ICV anti-LGI1 mAb infusion. Video-EEG recordings of juvenile rats uncovered two peaks of seizure frequency during the 7-day antibody infusion period resembling the natural progression of seizures in human anti-LGI1 encephalitis.Our data strongly corroborate and extend our understanding of the direct pathogenic and epileptogenic role of human LGI1 autoantibodies.
ISSN:08891591
DOI:10.1016/j.bbi.2025.02.019