NMDA-receptor antibodies alter cortical microcircuit dynamics

Richard E Rosch, Sukhvir Wright, Gerald Cooray, Margarita Papadopoulou, Sushma Goyal, Ming Lim, Angela Vincent, A Louise Upton, Torsten Baldeweg, Karl J Friston

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)E9916-E9925
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number42
Early online date27 Sep 2018
DOIs
Publication statusPublished - 16 Oct 2018

Bibliographical note

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).

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