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A new study published in the Journal of Nature looked at structural and functional mechanisms of learning and memory.

“NMDA receptors are essential for the fundamental processes,” study author Hiro Furukawa told us. “Recent clinical studies have revealed that in autoimmune encephalitis, antibodies targeting NMDA receptors disrupt normal neuronal function, resulting in psychotic symptoms.” 

For the first time, researchers have visualized the binding patterns of anti-NMDA receptor antibodies from patients with anti-NMDA receptor encephalitis using cryo-electron microscopy (cryo-EM). Additionally, they characterized the functional impact of these antibodies on NMDA receptor activity through electrophysiological recordings and imaging techniques. 

“Our collaborator in Germany isolated three antibodies from three different patients, and we aimed to determine whether these antibodies exhibited similar or distinct binding patterns and functional effects on NMDA receptors,” Furukawa told us.

The research hypothesized that the three antibodies would exhibit distinct binding patterns to NMDA receptors, as they are encoded by different DNA sequences.

“For many years, we have been the experts in the structural and functional analysis of NMDA receptors,” Furukawa told us. “From the moment the first clinical report on anti-NMDA receptor encephalitis emerged in 2007, we recognized that our expertise could contribute significantly to this field.”

The research team visualized the NMDA receptor antibody interactions at the atomic level using cryo-EM.

“We observed distinct binding patterns for the three autoimmune antibodies, each targeting different regions of the NMDA receptors,” Furukawa told us. “These unique interactions consequently influenced NMDA receptor function in varied ways.”

While the results weren’t surprising, Furukawa felt a sense of satisfaction in finally being able to visualize the antibody-NMDA receptor interactions.

“We now understand that no single, defined molecular mechanism is underlying this disease,” Furukawa told us. “However, with our capability to analyze antibody-NMDA receptor interactions, we can extend our research to include more patient-derived antibodies. We hope to raise awareness and encourage greater collaboration with clinicians. As we gather more data, we aim to identify commonalities among anti-NMDA receptor antibodies, which could inform the development of targeted therapeutic strategies.”

Furukawa is committed to raising awareness about this disease and fostering increased collaboration with clinicians. 

“We now have robust methods to detect these antibodies, isolate antibody-producing cells for DNA sequencing, and monitor NMDA receptor–antibody interactions at the atomic level.”