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

Ceanga, M.; Rahmati, V.; Haselmann, H.; Schmidl, L.; Hunter, D.; Kreye, J.; Pruess, H.; Groc, L.; Hallermann, S.; Dalmau, J.; Ori, A.; Heckmann, M.; Geis, C.

doi:10.1101/2022.03.04.482796

bioRxiv · 10.1101/2022.03.04.482796

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

Ceanga, M.·Rahmati, V.·Haselmann, H.·Schmidl, L.·Hunter, D.·Kreye, J.·Pruess, H.·Groc, L.·Hallermann, S.·Dalmau, J.·Ori, A.·Heckmann, M.·Geis, C.

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Abstract

Specific autoantibodies against the NMDA-receptor (NMDAR) GluN1 subunit cause severe and debilitating NMDAR-encephalitis. Autoantibodies induce prototypic disease symptoms resembling schizophrenia, including psychosis and cognitive dysfunction. Using a mouse passive transfer model applying human monoclonal anti-GluN1-autoantibodies, we observed CA1 pyramidal neuron hypoexcitability, reduced AMPA-receptor (AMPAR) signaling, and faster synaptic inhibition resulting in disrupted excitatory-inhibitory balance. Functional alterations were supported by widespread remodeling of the hippocampal proteome, including changes in glutamatergic and GABAergic neurotransmission. At the network level, anti-GluN1-autoantibodies amplified gamma oscillations and disrupted theta-gamma coupling. A data-informed network model revealed that lower AMPAR strength and faster GABAA-receptor current kinetics chiefly account for these abnormal oscillations. As predicted by our model and evidenced experimentally, positive allosteric modulation of AMPARs alleviated aberrant gamma activity and thus reinforced the causative effects of the excitatory-inhibitory imbalance. Collectively, NMDAR-hypofunction-induced aberrant synaptic, cellular, and network dynamics provide new mechanistic insights into disease symptoms in NMDAR-encephalitis and schizophrenia.

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Ceanga, M., Rahmati, V., Haselmann, H., Schmidl, L., Hunter, D., Kreye, J., Pruess, H., Groc, L., Hallermann, S., Dalmau, J., Ori, A., Heckmann, M., Geis, C.. 2022-03-07. Human NMDAR autoantibodies disrupt excitatory-inhibitory balance leading to hippocampal network hypersynchrony. https://doi.org/10.1101/2022.03.04.482796

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