Vignesh Subramanian ’24

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels whose signaling enables higher-order functions, such as learning and memory, throughout the brain. They are activated by glutamate, the major excitatory neurotransmitter in the central nervous system, and are dynamically distributed across synaptic and extrasynaptic sites. The obligate composition of these protein receptors includes two subunits known as GluN1 paired with combinations of spliced regulatory subunits – such as GluN2A and GluN2B – containing distinct extracellular domains. These domains typically mediate excitotoxicity, which occurs upon excessive stimulation of neurotransmitter receptors and causes mass neuronal damage and death. However, various acute, chronic, and neuropsychiatric brain disorders are associated with autoantibodies being directed against the aforementioned subunits, triggering numerous channelopathies. To better understand the relationship between autoimmune action and dysfunction in NMDAR-mediated signaling, a study led by Dr. Wollmuth of Stony Brook University characterized well-known anti-NMDAR autoantibodies.

Researchers conducted a meta-analysis of studies investigating the autoantibodies associated with the progression of anti-NMDAR encephalitis and systemic lupus erythematosus (SLE). Using nucleic acid stains to trace diffusion patterns, these studies found that encephalitis, a form of brain inflammation whose hallmarks include a flu-like malaise and forms of psychosis, is strongly associated with anti-GluN1 autoantibody action against a hinge region epitope, the antigen region at which the antibody attaches. The ensuing response disrupts the interaction between NMDARs and transsynaptic anchoring proteins, causing cross-linking and internalization of receptors as well as chronic decreases in excitatory postsynaptic currents and long-term potentiation, the process of strengthening synapses for which NMDARs are responsible. These effects suggest that anti-GluN1 autoantibodies induce the mechanistic feature of NMDAR hypofunction, which theoretically drives psychosis and seizures. The studies also found that SLE, characterized by various somatic and neuropsychiatric symptoms, is associated with anti-GluN2 autoantibody action against a particular peptide epitope known as DWEYS. CSF samples from SLE patients and DWEYS-immunized, LPS-treated mouse models revealed that the ensuing response involved the disruption of the blood-brain barrier and hippocampal localization of DNRAbs, a specific class of anti-GluN2 autoantibodies, triggering neuronal apoptosis. It correlated with region-associated behavioral deficits and memory impairment.

Such advances in studying the modes of action of key anti-NMDAR autoantibodies pave the way for a better understanding of their underlying pathophysiology and clinical phenotypes. Future studies might explore factors like circuit functions, clonal variations, and transitions between acute and long-term effects that add to the diversity of these autoantibodies and have complicated their classification thus far.

Works Cited:

[1] L. Wollmuth, et al., The diverse and complex modes of action of anti-NMDA receptor autoantibodies. Neuropharmacology 194, 1-10 (2021). doi: 10.1016/j.neuropharm.2021.108624

[2] Image retrieved from: https://commons.wikimedia.org/wiki/File:NMDA_receptor.jpg