Journal Article

DZNE-2026-00541

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The functional impact of LGI1 autoantibodies on human CA3 pyramidal neurons.

Monni, L. ; Kornau, H.-C.DZNE* ; Podestà, A. ; Sammons, R. P. ; Sannio, A. ; Stumpf, A. ; Kalbhenn, T. ; Simon, M. ; Sauvigny, T. ; Onken, J. ; Prüß, H.Extern* ; Geiger, J. R. P. ; Holtkamp, M. ; Schmitz, D. (Last author)DZNE* ; Fidzinski, P.

2026
National Acad. of Sciences Washington, DC

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Please use a persistent id in citations: doi:10.1073/pnas.2510121123

Abstract: Autoantibodies against leucine-rich glioma inactivated 1 protein (LGI1) lead to limbic encephalitis, a rare neurological autoimmune disorder characterized by faciobrachial dystonic seizures and memory deficits. While animal models provide precious insights into the mechanisms of LGI1 autoantibody action, species-specific confirmation is lacking. In this study, we investigated the effects of patient-derived LGI1 monoclonal antibodies (LGI1 mAb) on CA3 pyramidal neurons using cultured ex vivo human hippocampal slices, providing a unique platform to study disease mechanisms in a homologous, clinically relevant context. Under incubation conditions, human CA3 neurons preserved their morphology, were intrinsically excitable and received spontaneous excitatory currents with large amplitudes and frequencies suggestive of 'giant' AMPA receptor-mediated currents. In slices exposed to LGI1 mAb, human CA3 pyramidal neurons displayed increased action potential (AP) firing frequency, mirroring the effects observed with the Kv1.1 channel blocker dendrotoxin-K (DTX-K). This increase likely resulted from a decreased Kv1.1 channel activity at the axonal initial segment, as indicated by alterations in AP properties, including spike latency at rheobase and depolarizing ramp slope. Differences between LGI1 mAb and DTX-K effects on some AP properties suggested distinct mechanisms of action and emphasized the need for further exploration of downstream pathways. Our findings underscore the importance of species-specific confirmatory studies of disease mechanisms and give insight into possibilities and limitations of human hippocampal slice cultures as a translational model for the investigation of disease mechanisms beyond epilepsy, including the effects of pharmacological compounds and autoantibodies.

Keyword(s): Humans (MeSH) ; Autoantibodies: immunology (MeSH) ; Pyramidal Cells: immunology (MeSH) ; Pyramidal Cells: drug effects (MeSH) ; Intracellular Signaling Peptides and Proteins (MeSH) ; CA3 Region, Hippocampal: immunology (MeSH) ; CA3 Region, Hippocampal: cytology (MeSH) ; Proteins: immunology (MeSH) ; Action Potentials: drug effects (MeSH) ; Antibodies, Monoclonal: pharmacology (MeSH) ; Antibodies, Monoclonal: immunology (MeSH) ; Limbic Encephalitis: immunology (MeSH) ; Animals (MeSH) ; CA3 pyramidal neurons ; LGI1 autoantibodies ; electrophysiology ; hippocampus ; human ; Autoantibodies ; LGI1 protein, human ; Intracellular Signaling Peptides and Proteins ; Proteins ; Antibodies, Monoclonal

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Contributing Institute(s):

1. Network Dysfunction (AG Schmitz)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; National-Konsortium ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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