NMDA receptor autoantibodies primarily impair the extrasynaptic compartment

Area of Science:

• Neuroimmunology
• Molecular Neuroscience
• Cell Biology

Background:

• Autoantibodies against the N-methyl-D-aspartate receptor (NMDAR-Ab) are key in NMDAR encephalitis, causing neurological and psychiatric symptoms.
• The precise early molecular mechanisms by which NMDAR-Ab induce brain dysfunction remain poorly understood.
• Existing knowledge of NMDAR-Ab's early actions on neuronal networks is fragmented.

Purpose of the Study:

• To elucidate the spatiotemporal effects of NMDAR-Ab on live hippocampal neurons using advanced imaging.
• To investigate the initial molecular targets and cascade initiated by NMDAR-Ab.
• To differentiate the impact of NMDAR-Ab on extrasynaptic versus synaptic NMDARs.

Main Methods:

• Single molecule-based imaging of membrane proteins on live hippocampal neurons.
• Analysis of NMDAR membrane dynamics and protein interactions.
• Investigating the role of EphB2 receptor in NMDAR-Ab-mediated effects.

Main Results:

• NMDAR-Ab primarily target extrasynaptic NMDARs, increasing their membrane dynamics and declustering their interactome within minutes.
• NMDAR-Ab rapidly alter the distribution of multiple membrane proteins in the extrasynaptic compartment.
• Long-term effects include reduced synaptic NMDARs due to slowed receptor dynamics, independent of cross-linking.
• Targeting extrasynaptic NMDARs alone was sufficient to elicit effects on synaptic receptors.

Conclusions:

• NMDAR-Ab initiate pathogenic effects by first impairing extrasynaptic proteins, subsequently affecting synaptic components.
• This study provides novel insights into the early mode of action of NMDAR-Ab.
• Findings contribute to understanding the pathophysiology of NMDAR encephalitis and related (extra)synaptopathies.