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

• DOI: 10.1016/j.celrep.2023.113166
• Publication Date: 2023-09-27T16:36:30Z
• Authors: Mihai Ceanga; Vahid Rahmati; Holger Haselmann; Lars Schmidl; Daniel Hunter; Anna-Katherina Br...; Sabine Liebscher; Jakob Kreye; Harald Prüss; Laurent Groc; Stefan Hallermann; Josep Dalmau; Alessandro Ori; Manfred Heckmann; Christian Geis
• Keywords: θ-γ coupling; autoantibodies; QH301-705.5; neural network modeling; NMDA receptor encephalitis; microglia; metabolism [Hippocampus]; Hippocampus; Synaptic Transmission; Receptors, N-Methyl-D-Aspartate; Mice; Humans; Animals; ddc:610; Receptors, AMPA; Biology (General); metabolism [Receptors, N-Methyl-D-Aspartate]; Autoantibodies; Neurons; Neuroscience [CP]; metabolism [Receptors, AMPA]; NMDA receptor; network oscillation; 3. Good health; metabolism [Neurons]; CP: Neuroscience; excitatory-inhibitory imbalance

Anti-NMDA receptor autoantibodies (NMDAR-Abs) in patients with NMDAR encephalitis cause severe disease symptoms resembling psychosis and cognitive dysfunction. After passive transfer of patients' cerebrospinal fluid or human monoclonal anti-GluN1-autoantibodies mice, we find a disrupted excitatory-inhibitory balance resulting from CA1 neuronal hypoexcitability, reduced AMPA (AMPAR) signaling, faster synaptic inhibition acute hippocampal slices. Functional alterations are also reflected widespread remodeling the proteome, including changes glutamatergic GABAergic neurotransmission. NMDAR-Abs amplify network γ oscillations disrupt θ-γ coupling. A data-informed model reveals that lower AMPAR strength GABAA current kinetics chiefly account for these abnormal oscillations. As predicted silico evidenced ex vivo, positive allosteric modulation AMPARs alleviates aberrant activity, reinforcing causative effects imbalance. Collectively, NMDAR-Ab-induced synaptic, cellular, dynamics provide conceptual insights into NMDAR-Ab-mediated pathomechanisms reveal promising therapeutic targets merit future vivo validation.