Positive Allosteric Modulation of NMDARs Prevents the Altered Surface Dynamics Caused by Patients' Antibodies.
Neurol Neuroimmunol Neuroinflamm
; 11(4): e200261, 2024 Jul.
Article
in En
| MEDLINE
| ID: mdl-38771989
ABSTRACT
OBJECTIVES:
A positive allosteric modulator of the NMDAR, SGE-301, has been shown to reverse the alterations caused by the antibodies of patients with anti-NMDAR encephalitis (NMDARe). However, the mechanisms involved beyond receptor modulation are unclear. In this study, we aimed to investigate how this modulator affects NMDAR membrane dynamics.METHODS:
Cultured hippocampal neurons were treated with SGE-301 or vehicle, alongside with immunoglobulins G (IgG) from patients with NMDARe or healthy controls. NMDAR surface dynamics were assessed with single-molecule imaging by photoactivated localization microscopy.RESULTS:
NMDAR trajectories from neurons treated with SGE-301 were less confinement, with increased diffusion coefficients. This effect mainly occurred at synapses because extrasynaptic diffusion and confinement were minimally affected by SGE-301. Treatment with patients' IgG reduced NMDAR surface dynamics and increased their confinement. Remarkably, SGE-301 incubation antagonized patients' IgG effects in both synaptic and extrasynaptic membrane compartments, restoring diffusion and confinement values similar to those from neurons exposed to control IgG.DISCUSSION:
We demonstrate that SGE-301 upregulates NMDAR surface diffusion and antagonizes the pathogenic effects of patients' IgG on NMDAR membrane organization. These findings suggest a potential therapeutic strategy for NMDARe.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Immunoglobulin G
/
Receptors, N-Methyl-D-Aspartate
/
Anti-N-Methyl-D-Aspartate Receptor Encephalitis
/
Hippocampus
/
Neurons
Limits:
Adult
/
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Neurol Neuroimmunol Neuroinflamm
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: