Human NMDAR autoantibodies disrupt excitatory-inhibitory balance, leading to hippocampal network hypersynchrony

Ceanga, Mihai; Rahmati, Vahid; Haselmann, Holger; Schmidl, Lars; Hunter, Daniel; Brauer, Anna-Katherina; Liebscher, Sabine; Kreye, Jakob; Pruess, Harald; Groc, Laurent; Hallermann, Stefan; Dalmau, Josep; Ori, Alessandro; Heckmann, Manfred und Geis, Christian (2023): Human NMDAR autoantibodies disrupt excitatory-inhibitory balance, leading to hippocampal network hypersynchrony. In: Cell Reports, Bd. 42, Nr. 10, 113166

Abstract

Anti-NMDA receptor autoantibodies (NMDAR-Abs) in patients with NMDAR encephalitis cause severe dis-ease 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 excit-atory-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 g oscillations and disrupt q -g coupling. A data-informed network model reveals that lower AMPAR strength and faster GABAA receptor current kinetics chiefly ac-count for these abnormal oscillations. As predicted in silico and evidenced ex vivo, positive allosteric mod-ulation of AMPARs alleviates aberrant g activity, reinforcing the causative effects of the excitatory-inhibitory imbalance. Collectively, NMDAR-Ab-induced aberrant synaptic, cellular, and network dynamics provide con-ceptual insights into NMDAR-Ab-mediated pathomechanisms and reveal promising therapeutic targets that merit future in vivo validation.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198