NMDA-receptor antibodies alter cortical microcircuit dynamics

Abstract

NMDA-receptor antibodies (NMDAR-Abs) cause an autoimmune encephalitis with a diverse range of EEG abnormalities. NMDAR-Abs are believed to disrupt receptor function, but how blocking this excitatory synaptic receptor can lead to paroxysmal EEG abnormalities-or even seizures-is poorly understood. Here we show that NMDAR-Abs change intrinsic cortical connections and neuronal population dynamics to alter the spectral composition of spontaneous EEG activity and predispose brain dynamics to paroxysmal abnormalities. Based on local field potential recordings in a mouse model, we first validate a dynamic causal model of NMDAR-Ab effects on cortical microcircuitry. Using this model, we then identify the key synaptic parameters that best explain EEG paroxysms in pediatric patients with NMDAR-Ab encephalitis. Finally, we use the mouse model to show that NMDAR-Ab-related changes render microcircuitry critically susceptible to overt EEG paroxysms when these key parameters are changed, even though the same parameter fluctuations are tolerated in the in silico model of the control condition. These findings offer mechanistic insights into circuit-level dysfunction induced by NMDAR-Ab.

Publication DOI: https://doi.org/10.1073/pnas.1804846115
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences
College of Engineering & Physical Sciences > School of Infrastructure and Sustainable Engineering > Engineering Systems and Supply Chain Management
Additional Information: Copyright © 2018 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Publication ISSN: 1091-6490
Full Text Link:
Related URLs: http://www.pnas ... 9/26/1804846115 (Publisher URL)
https://www.doi ... 5/OSF.IO/YXKWD. (Related URL)
PURE Output Type: Article
Published Date: 2018-10-16
Published Online Date: 2018-09-27
Accepted Date: 2018-08-29
Authors: Rosch, Richard E
Wright, Sukhvir (ORCID Profile 0000-0002-5464-3779)
Cooray, Gerald
Papadopoulou, Margarita
Goyal, Sushma
Lim, Ming
Vincent, Angela
Upton, A Louise
Baldeweg, Torsten
Friston, Karl J

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