Journal Article

DZNE-2023-01000

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Human NMDAR autoantibodies disrupt excitatory-inhibitory balance, leading to hippocampal network hypersynchrony

Ceanga, M. ; Rahmati, V. ; Haselmann, H. ; Schmidl, L. ; Hunter, D. ; Brauer, A.-K. ; Liebscher, S. ; Kreye, J.DZNE* ; Prüss, H.DZNE* ; Groc, L. ; Hallermann, S. ; Dalmau, J. ; Ori, A. ; Heckmann, M. ; Geis, C.

2023
Elsevier [New York, NY]

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Please use a persistent id in citations: doi:10.1016/j.celrep.2023.113166

Abstract: 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.

Keyword(s): Humans (MeSH) ; Mice (MeSH) ; Animals (MeSH) ; Hippocampus: metabolism (MeSH) ; Synaptic Transmission (MeSH) ; Receptors, N-Methyl-D-Aspartate: metabolism (MeSH) ; Neurons: metabolism (MeSH) ; Autoantibodies (MeSH) ; Receptors, AMPA: metabolism (MeSH) ; θ-γ coupling ; θ-γ coupling ; CP: Neuroscience ; NMDA receptor ; NMDA receptor encephalitis ; autoantibodies ; excitatory-inhibitory imbalance ; microglia ; network oscillation ; neural network modeling ; θ-γ coupling ; Receptors, N-Methyl-D-Aspartate ; Autoantibodies ; Receptors, AMPA

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Contributing Institute(s):

1. Autoimmune Encephalopathies (AG Prüß)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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