NMDA-receptor antibodies alter cortical microcircuit dynamics

Abstract

NMDA-receptor antibodies (NMDAR-Ab) cause an autoimmune encephalitis with a diverse range of electroencephalographic (EEG) abnormalities. NMDAR-Ab are believed to disrupt receptor function, but how blocking this excitatory neurotransmitter can lead to paroxysmal EEG abnormalities – or even seizures – is poorly understood. Here, we show that NMDAR-Ab change intrinsic cortical connections and neuronal population dynamics to alter the spectral composition of spontaneous EEG activity, and predispose to paroxysmal EEG 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 paediatric 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. These findings offer mechanistic insights into circuit-level dysfunction induced by NMDAR-Ab.

Differences in visually induced MEG oscillations reflect differences in deep cortical layer activity

“…This ensured the neural mass model has construct validity in relation to the compartmental model. DCM approach has been used to infer changes in synaptic plasticity in large cortical networks 17 in healthy and clinical populations 19 among other applications. It exploits the stationarity of variance of neuronal firing over the course of the task to efficiently fit neural mass models to MEG data.…”

In vitrocharacterisation and neurosteroid treatment of an N-Methyl-D-Aspartate receptor antibody-mediated seizure model

“…Despite the symptom predominance of seizures in humans, producing reliable and consistent spontaneous seizure animal models of this disorder using passive transfer of human-derived antibodies is challenging (18)(19)(20). In our previous passive transfer mouse model, we demonstrated increased in vivo seizure susceptibility (and therefore network hyperexcitability) 48 hours after intracerebroventricular NMDAR-Ab injection compared to controls, however spontaneous seizures were not seen (18,21).…”

“…All analysis code and raw data are available online at http://doi.org/ 2010.17605/OSF.IO/GUPBF. Analogous to previous work (21,78), we modelled LFP spectra recorded in rat hippocampal tissue as arising from a single canonical microcircuit at steady state (79). This 'canonical microcircuit' is a layered set of recurrently coupled excitatory and inhibitory neural masses (80)(81)(82).…”

Differences in visually induced MEG oscillations reflect differences in deep cortical layer activity

“…This ensured the neural mass model has construct validity in relation to the compartmental model. DCM approach has been used to infer changes in synaptic plasticity in large cortical networks [11] in healthy and clinical populations [13] among other applications. It exploits the stationarity of variance of neuronal firing over the course of the task to efficiently fit neural mass models to MEG data.…”