# NMDA receptor autoantibodies primarily impair the extrasynaptic compartment

## TL;DR

This study shows that NMDA receptor autoantibodies first disrupt proteins outside synapses, leading to later synaptic effects, which helps explain early brain dysfunction in NMDAR encephalitis.

## Contribution

The study reveals that NMDAR-Ab initially target extrasynaptic proteins, not just synaptic ones, and this mechanism is not solely mediated by EphB2.

## Key findings

- NMDAR-Ab primarily affect extrasynaptic NMDARs, increasing their membrane dynamics and declustering their surface interactome.
- NMDAR-Ab rapidly reshuffle all membrane proteins in the extrasynaptic compartment within minutes.
- Long-term exposure reduces synaptic NMDARs by slowing receptor membrane dynamics, independent of cross-linking.

## Abstract

Autoantibodies directed against the N-methyl-D-aspartate receptor (NMDAR-Ab) are pathogenic immunoglobulins detected in patients suffering from NMDAR encephalitis. NMDAR-Ab alter the receptor membrane trafficking, synaptic transmission and neuronal network properties, leading to neurological and psychiatric symptoms in patients. Patients often have very little neuronal damage but rapid and massive (treatment-responsive) brain dysfunctions related to an unknown early mechanism of NMDAR-Ab. Our understanding of this early molecular cascade remains surprisingly fragmented.

Here, we used a combination of single molecule-based imaging of membrane proteins to unveil the spatiotemporal action of NMDAR-Ab on live hippocampal neurons.

We first demonstrate that different clones of NMDAR-Ab primarily affect extrasynaptic (and not synaptic) NMDARs. In the first minutes, NMDAR-Ab increase extrasynaptic NMDAR membrane dynamics, declustering its surface interactome. NMDAR-Ab also rapidly reshuffle all membrane proteins located in the extrasynaptic compartment. Consistent with this alteration of multiple proteins, effects of NMDAR-Ab were not mediated through the sole interaction between the NMDAR and EphB2 receptor. In the long term, NMDAR-Ab reduce the NMDAR synaptic pool by slowing down receptor membrane dynamics in a cross-linking-independent manner. Remarkably, exposing only extrasynaptic NMDARs to NMDAR-Ab was sufficient to produce their full-blown effect on synaptic receptors.

Collectively, we demonstrate that NMDAR-Ab initially impair extrasynaptic proteins, then the synaptic ones. These data thus shed new and unsuspected light on the mode of action of NMDAR-Ab and, probably, our understanding of (extra)synaptopathies.

Jamet et al. explore the effects of autoantibodies against the NMDA receptor on rodent hippocampal neurons. They describe the molecular cascade triggered by the autoantibodies in the first minutes to hours of exposure, and show that the autoantibodies initially target the extrasynaptic compartment.

See Zhao et al. (https://doi.org/10.1093/brain/awae236) for a scientific commentary on this article.