N-methyl-D-aspartate receptors (NMDARs) are a class of neurotransmitter receptors that bind glutamate, the major excitatory neurotransmitter in the brain. NMDARs support essential brain functions, including neuronal communication and development, learning, and memory. These receptors form a pore that allows the passage of essential ions like calcium and sodium across the neuron membrane to modulate neuronal activity. Indeed, through calcium-driven signalling, NMDARs are best known for regulating the strength of synapses (the communication points between neurons) in a process termed synaptic plasticity, which is thought to underly learning and memory. However, the advancement of imaging techniques in past years has further revealed that the role of NMDAR goes beyond their calcium permeability. The way NMDARs move around the cell surface and how they are organized at a nanoscale level in specialized domains can also significantly shape synaptic plasticity.
About 15 years ago, researchers found circulating antibodies targeting NMDARs (NMDAR-Abs) in patients with autoimmune encephalitis, schizophrenia and psychosis, and which cause severe psychiatric, cognitive and neurological symptoms. This remarkable discovery reshaped how several neurological and psychiatric disorders are diagnosed and further substantiated the idea that NMDAR function is more than being an ion channel. At the cellular level, the antibodies disturb the nanoscale organization and surface diffusion of NMDARs, causing the receptors to be internalized. This reduces NMDAR function and weakens synaptic plasticity, even though calcium flow through the receptors remains unchanged, once again corroborating an ionotropic-independent role of NMDARs. A puzzling clinical feature of NMDAR-Abs is that many patients also experience seizures, associated with neuronal hyperexcitation, despite the antibody-induced reduction of NMDAR excitatory function. Indeed, NMDAR-Abs make cells more excitable (meaning that they are more easily activated) and cause excessive excitation in hippocampal networks, explaining the seizures. However, the mechanisms behind this particular effect of the NMDAR-Abs are still not understood.
Considering the relevance of NMDARs in the regulation of multiple neuronal dimensions and their implication in several neurological/psychiatric disorders, it is essential that we learn the full landscape of NMDAR physiology to understand their associated pathology. One key piece of knowledge that is missing so far is the characterization of the surface environment (where NMDAR-Abs act, for instance) surrounding NMDARs, including knowing who their neighbors are and how they behave at the cell surface as well. In this project, we aimed to do precisely this. By employing advanced biochemical and super-resolution microscopy approaches, we aimed at creating a snapshot of the surface interactome of NMDARs and investigate how it might be remodeled in the presence of NMDAR-Abs.
Identifying important interactors of NMDARs (which could potentially also be corrupted by NMDAR-Abs) will not only provide further insight into the physiological role of NMDARs but also shed light on the full pathogenic mechanisms elicited by the antibodies.
