Human NMDAR autoantibodies disrupt excitatory-inhibitory balance, leading to hippocampal network hypersynchrony
Mihai Ceanga,
Vahid Rahmati,
Holger Haselmann,
Lars Schmidl,
Daniel Hunter,
Anna-Katherina Brauer,
Sabine Liebscher,
Jakob Kreye,
Harald Prüss,
Laurent Groc,
Stefan Hallermann,
Josep Dalmau,
Alessandro Ori,
Manfred Heckmann,
Christian Geis
Affiliations
Mihai Ceanga
Section of Translational Neuroimmunology, Department of Neurology, Jena University Hospital, 07747 Jena, Germany
Vahid Rahmati
Section of Translational Neuroimmunology, Department of Neurology, Jena University Hospital, 07747 Jena, Germany
Holger Haselmann
Section of Translational Neuroimmunology, Department of Neurology, Jena University Hospital, 07747 Jena, Germany
Lars Schmidl
Section of Translational Neuroimmunology, Department of Neurology, Jena University Hospital, 07747 Jena, Germany
Daniel Hunter
Université de Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France
Anna-Katherina Brauer
Institute of Clinical Neuroimmunology, Klinikum der Universität München, Ludwig Maximilians University Munich, Martinsried, Germany; Biomedical Center, Ludwig Maximilians University Munich, Martinsried, Germany
Sabine Liebscher
Institute of Clinical Neuroimmunology, Klinikum der Universität München, Ludwig Maximilians University Munich, Martinsried, Germany; Biomedical Center, Ludwig Maximilians University Munich, Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Jakob Kreye
Department of Neurology and Experimental Neurology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany; Department of Pediatric Neurology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Harald Prüss
Department of Neurology and Experimental Neurology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany
Laurent Groc
Université de Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, 33000 Bordeaux, France
Stefan Hallermann
Carl Ludwig Institute for Physiology, Faculty of Medicine, Leipzig University, 04103 Leipzig, Germany
Josep Dalmau
Catalan Institution for Research and Advanced Studies (ICREA) and IDIBAPS-Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain
Alessandro Ori
Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), 07745 Jena, Germany
Manfred Heckmann
Department of Neurophysiology, Institute of Physiology, University of Würzburg, 97070 Würzburg, Germany
Christian Geis
Section of Translational Neuroimmunology, Department of Neurology, Jena University Hospital, 07747 Jena, Germany; Corresponding author
Summary: Anti-NMDA receptor autoantibodies (NMDAR-Abs) in patients with NMDAR encephalitis cause severe disease symptoms resembling psychosis and cause cognitive dysfunction. After passive transfer of patients’ cerebrospinal fluid or human monoclonal anti-GluN1-autoantibodies in mice, we find a disrupted excitatory-inhibitory balance resulting from CA1 neuronal hypoexcitability, reduced AMPA receptor (AMPAR) signaling, and faster synaptic inhibition in acute hippocampal slices. Functional alterations are also reflected in widespread remodeling of the hippocampal proteome, including changes in glutamatergic and GABAergic neurotransmission. NMDAR-Abs amplify network γ oscillations and disrupt θ-γ coupling. A data-informed network model reveals that lower AMPAR strength and faster GABAA receptor current kinetics chiefly account for these abnormal oscillations. As predicted in silico and evidenced ex vivo, positive allosteric modulation of AMPARs alleviates aberrant γ activity, reinforcing the causative effects of the excitatory-inhibitory imbalance. Collectively, NMDAR-Ab-induced aberrant synaptic, cellular, and network dynamics provide conceptual insights into NMDAR-Ab-mediated pathomechanisms and reveal promising therapeutic targets that merit future in vivo validation.
