LGI1 Autoantibodies Enhance Synaptic Transmission by Presynaptic K

Autoantibodies / immunology Humans Animals Synaptic Transmission / physiology Intracellular Signaling Peptides and Proteins / immunology Presynaptic Terminals / metabolism Action Potentials / physiology Hippocampus / metabolism Rats Kv1.1 Potassium Channel / immunology Proteins / immunology Male Cells, Cultured

Journal

Neurology(R) neuroimmunology & neuroinflammation
ISSN: 2332-7812
Titre abrégé: Neurol Neuroimmunol Neuroinflamm
Pays: United States
ID NLM: 101636388

Informations de publication

Date de publication:
Sep 2024
Historique:
medline: 14 8 2024
pubmed: 14 8 2024
entrez: 14 8 2024
Statut: ppublish

Résumé

Autoantibodies against the protein leucine-rich glioma inactivated 1 (LGI1) cause the most common subtype of autoimmune encephalitis with predominant involvement of the limbic system, associated with seizures and memory deficits. LGI1 and its receptor ADAM22 are part of a transsynaptic protein complex that includes several proteins involved in presynaptic neurotransmitter release and postsynaptic glutamate sensing. Autoantibodies against LGI1 increase excitatory synaptic strength, but studies that genetically disrupt the LGI1-ADAM22 complex report a reduction in postsynaptic glutamate receptor-mediated responses. Thus, the mechanisms underlying the increased synaptic strength induced by LGI1 autoantibodies remain elusive, and the contributions of presynaptic molecules to the LGI1-transsynaptic complex remain unclear. We therefore investigated the presynaptic mechanisms that mediate autoantibody-induced synaptic strengthening. We studied the effects of patient-derived purified polyclonal LGI1 autoantibodies on synaptic structure and function by combining direct patch-clamp recordings from presynaptic boutons and somata of hippocampal neurons with super-resolution light and electron microscopy of hippocampal cultures and brain slices. We also identified the protein domain mediating the presynaptic effect using domain-specific patient-derived monoclonal antibodies. LGI1 autoantibodies dose-dependently increased short-term depression during high-frequency transmission, consistent with increased release probability. The increased neurotransmission was not related to presynaptic calcium channels because presynaptic Ca Our results indicate that LGI1 autoantibodies reduce the density of both K

Sections du résumé

BACKGROUND AND OBJECTIVES OBJECTIVE
Autoantibodies against the protein leucine-rich glioma inactivated 1 (LGI1) cause the most common subtype of autoimmune encephalitis with predominant involvement of the limbic system, associated with seizures and memory deficits. LGI1 and its receptor ADAM22 are part of a transsynaptic protein complex that includes several proteins involved in presynaptic neurotransmitter release and postsynaptic glutamate sensing. Autoantibodies against LGI1 increase excitatory synaptic strength, but studies that genetically disrupt the LGI1-ADAM22 complex report a reduction in postsynaptic glutamate receptor-mediated responses. Thus, the mechanisms underlying the increased synaptic strength induced by LGI1 autoantibodies remain elusive, and the contributions of presynaptic molecules to the LGI1-transsynaptic complex remain unclear. We therefore investigated the presynaptic mechanisms that mediate autoantibody-induced synaptic strengthening.
METHODS METHODS
We studied the effects of patient-derived purified polyclonal LGI1 autoantibodies on synaptic structure and function by combining direct patch-clamp recordings from presynaptic boutons and somata of hippocampal neurons with super-resolution light and electron microscopy of hippocampal cultures and brain slices. We also identified the protein domain mediating the presynaptic effect using domain-specific patient-derived monoclonal antibodies.
RESULTS RESULTS
LGI1 autoantibodies dose-dependently increased short-term depression during high-frequency transmission, consistent with increased release probability. The increased neurotransmission was not related to presynaptic calcium channels because presynaptic Ca
DISCUSSION CONCLUSIONS
Our results indicate that LGI1 autoantibodies reduce the density of both K

Identifiants

DOI: 10.1212/NXI.0000000000200284 PMID: 39141878
pubmed: 39141878
doi: 10.1212/NXI.0000000000200284
doi:

Substances chimiques

Autoantibodies 0
LGI1 protein, human 0
Intracellular Signaling Peptides and Proteins 0
Kv1.1 Potassium Channel 147173-20-4
Proteins 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

e200284

Auteurs

Andreas Ritzau-Jost (A)

From the Carl-Ludwig-Institute of Physiology (A.R.-J., F.G., T.K., S.M., S.H.), Faculty of Medicine, Leipzig University; Section Translational Neuroimmunology (J.S., C.G.), Department of Neurology, Jena University Hospital; Department of Biotechnology and Biophysics (S.S., C.W., M.S.), University of Würzburg, Biocenter, Germany; Institute of Science and Technology Austria (ISTA) (J.M., R.S.), Klosterneuburg, Austria; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, ; Department of Neurology (S.R.I.), John Radcliffe Hospital, Oxford University Hospitals, United Kingdom; and Departments of Neurology and Neurosciences (S.R.I.), Mayo Clinic Jacksonville, FL.

Felix Gsell (F)

From the Carl-Ludwig-Institute of Physiology (A.R.-J., F.G., T.K., S.M., S.H.), Faculty of Medicine, Leipzig University; Section Translational Neuroimmunology (J.S., C.G.), Department of Neurology, Jena University Hospital; Department of Biotechnology and Biophysics (S.S., C.W., M.S.), University of Würzburg, Biocenter, Germany; Institute of Science and Technology Austria (ISTA) (J.M., R.S.), Klosterneuburg, Austria; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, ; Department of Neurology (S.R.I.), John Radcliffe Hospital, Oxford University Hospitals, United Kingdom; and Departments of Neurology and Neurosciences (S.R.I.), Mayo Clinic Jacksonville, FL.

Josefine Sell (J)

From the Carl-Ludwig-Institute of Physiology (A.R.-J., F.G., T.K., S.M., S.H.), Faculty of Medicine, Leipzig University; Section Translational Neuroimmunology (J.S., C.G.), Department of Neurology, Jena University Hospital; Department of Biotechnology and Biophysics (S.S., C.W., M.S.), University of Würzburg, Biocenter, Germany; Institute of Science and Technology Austria (ISTA) (J.M., R.S.), Klosterneuburg, Austria; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, ; Department of Neurology (S.R.I.), John Radcliffe Hospital, Oxford University Hospitals, United Kingdom; and Departments of Neurology and Neurosciences (S.R.I.), Mayo Clinic Jacksonville, FL.

Stefan Sachs (S)

From the Carl-Ludwig-Institute of Physiology (A.R.-J., F.G., T.K., S.M., S.H.), Faculty of Medicine, Leipzig University; Section Translational Neuroimmunology (J.S., C.G.), Department of Neurology, Jena University Hospital; Department of Biotechnology and Biophysics (S.S., C.W., M.S.), University of Würzburg, Biocenter, Germany; Institute of Science and Technology Austria (ISTA) (J.M., R.S.), Klosterneuburg, Austria; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, ; Department of Neurology (S.R.I.), John Radcliffe Hospital, Oxford University Hospitals, United Kingdom; and Departments of Neurology and Neurosciences (S.R.I.), Mayo Clinic Jacksonville, FL.

Jacqueline Montanaro (J)

From the Carl-Ludwig-Institute of Physiology (A.R.-J., F.G., T.K., S.M., S.H.), Faculty of Medicine, Leipzig University; Section Translational Neuroimmunology (J.S., C.G.), Department of Neurology, Jena University Hospital; Department of Biotechnology and Biophysics (S.S., C.W., M.S.), University of Würzburg, Biocenter, Germany; Institute of Science and Technology Austria (ISTA) (J.M., R.S.), Klosterneuburg, Austria; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, ; Department of Neurology (S.R.I.), John Radcliffe Hospital, Oxford University Hospitals, United Kingdom; and Departments of Neurology and Neurosciences (S.R.I.), Mayo Clinic Jacksonville, FL.

Toni Kirmann (T)

From the Carl-Ludwig-Institute of Physiology (A.R.-J., F.G., T.K., S.M., S.H.), Faculty of Medicine, Leipzig University; Section Translational Neuroimmunology (J.S., C.G.), Department of Neurology, Jena University Hospital; Department of Biotechnology and Biophysics (S.S., C.W., M.S.), University of Würzburg, Biocenter, Germany; Institute of Science and Technology Austria (ISTA) (J.M., R.S.), Klosterneuburg, Austria; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, ; Department of Neurology (S.R.I.), John Radcliffe Hospital, Oxford University Hospitals, United Kingdom; and Departments of Neurology and Neurosciences (S.R.I.), Mayo Clinic Jacksonville, FL.

Sebastian Maaß (S)

From the Carl-Ludwig-Institute of Physiology (A.R.-J., F.G., T.K., S.M., S.H.), Faculty of Medicine, Leipzig University; Section Translational Neuroimmunology (J.S., C.G.), Department of Neurology, Jena University Hospital; Department of Biotechnology and Biophysics (S.S., C.W., M.S.), University of Würzburg, Biocenter, Germany; Institute of Science and Technology Austria (ISTA) (J.M., R.S.), Klosterneuburg, Austria; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, ; Department of Neurology (S.R.I.), John Radcliffe Hospital, Oxford University Hospitals, United Kingdom; and Departments of Neurology and Neurosciences (S.R.I.), Mayo Clinic Jacksonville, FL.

Sarosh R Irani (SR)

From the Carl-Ludwig-Institute of Physiology (A.R.-J., F.G., T.K., S.M., S.H.), Faculty of Medicine, Leipzig University; Section Translational Neuroimmunology (J.S., C.G.), Department of Neurology, Jena University Hospital; Department of Biotechnology and Biophysics (S.S., C.W., M.S.), University of Würzburg, Biocenter, Germany; Institute of Science and Technology Austria (ISTA) (J.M., R.S.), Klosterneuburg, Austria; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, ; Department of Neurology (S.R.I.), John Radcliffe Hospital, Oxford University Hospitals, United Kingdom; and Departments of Neurology and Neurosciences (S.R.I.), Mayo Clinic Jacksonville, FL.
ORCID: 0000-0002-7667-9748

Christian Werner (C)

From the Carl-Ludwig-Institute of Physiology (A.R.-J., F.G., T.K., S.M., S.H.), Faculty of Medicine, Leipzig University; Section Translational Neuroimmunology (J.S., C.G.), Department of Neurology, Jena University Hospital; Department of Biotechnology and Biophysics (S.S., C.W., M.S.), University of Würzburg, Biocenter, Germany; Institute of Science and Technology Austria (ISTA) (J.M., R.S.), Klosterneuburg, Austria; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, ; Department of Neurology (S.R.I.), John Radcliffe Hospital, Oxford University Hospitals, United Kingdom; and Departments of Neurology and Neurosciences (S.R.I.), Mayo Clinic Jacksonville, FL.

Christian Geis (C)

From the Carl-Ludwig-Institute of Physiology (A.R.-J., F.G., T.K., S.M., S.H.), Faculty of Medicine, Leipzig University; Section Translational Neuroimmunology (J.S., C.G.), Department of Neurology, Jena University Hospital; Department of Biotechnology and Biophysics (S.S., C.W., M.S.), University of Würzburg, Biocenter, Germany; Institute of Science and Technology Austria (ISTA) (J.M., R.S.), Klosterneuburg, Austria; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, ; Department of Neurology (S.R.I.), John Radcliffe Hospital, Oxford University Hospitals, United Kingdom; and Departments of Neurology and Neurosciences (S.R.I.), Mayo Clinic Jacksonville, FL.
ORCID: 0000-0002-9859-581X

Markus Sauer (M)

From the Carl-Ludwig-Institute of Physiology (A.R.-J., F.G., T.K., S.M., S.H.), Faculty of Medicine, Leipzig University; Section Translational Neuroimmunology (J.S., C.G.), Department of Neurology, Jena University Hospital; Department of Biotechnology and Biophysics (S.S., C.W., M.S.), University of Würzburg, Biocenter, Germany; Institute of Science and Technology Austria (ISTA) (J.M., R.S.), Klosterneuburg, Austria; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, ; Department of Neurology (S.R.I.), John Radcliffe Hospital, Oxford University Hospitals, United Kingdom; and Departments of Neurology and Neurosciences (S.R.I.), Mayo Clinic Jacksonville, FL.

Ryuichi Shigemoto (R)

From the Carl-Ludwig-Institute of Physiology (A.R.-J., F.G., T.K., S.M., S.H.), Faculty of Medicine, Leipzig University; Section Translational Neuroimmunology (J.S., C.G.), Department of Neurology, Jena University Hospital; Department of Biotechnology and Biophysics (S.S., C.W., M.S.), University of Würzburg, Biocenter, Germany; Institute of Science and Technology Austria (ISTA) (J.M., R.S.), Klosterneuburg, Austria; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, ; Department of Neurology (S.R.I.), John Radcliffe Hospital, Oxford University Hospitals, United Kingdom; and Departments of Neurology and Neurosciences (S.R.I.), Mayo Clinic Jacksonville, FL.

Stefan Hallermann (S)

From the Carl-Ludwig-Institute of Physiology (A.R.-J., F.G., T.K., S.M., S.H.), Faculty of Medicine, Leipzig University; Section Translational Neuroimmunology (J.S., C.G.), Department of Neurology, Jena University Hospital; Department of Biotechnology and Biophysics (S.S., C.W., M.S.), University of Würzburg, Biocenter, Germany; Institute of Science and Technology Austria (ISTA) (J.M., R.S.), Klosterneuburg, Austria; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, University of Oxford, ; Department of Neurology (S.R.I.), John Radcliffe Hospital, Oxford University Hospitals, United Kingdom; and Departments of Neurology and Neurosciences (S.R.I.), Mayo Clinic Jacksonville, FL.
ORCID: 0000-0001-9376-7048

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Autoanticorps › LGI1 Autoantibodies Enhance Synaptic...
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