What do we know:
Our immune systems produce particles known as antibodies that bind to harmful or foreign matter in our bodies, targeting them for removal. Sometimes these antibodies incorrectly tag normal healthy things in our bodies as “bad,” like proteins on the surface of our neurons. This mistake can lead to diseases, such as a swelling of the brain called encephalitis.
What don’t we know: We don’t yet understand what happens to the neurons that antibodies mistakenly identify as “bad,” and whether those neurons still work well after this process.
What this study shows: When antibodies mistakenly tag a protein found on neurons that is important for learning and memory known as a NMDA receptor, the protein is sucked back into the cells and chewed up for disposal. In addition, affected neurons try to make up for these changes by changing their connections to other neurons.
What we can do in the future because of this study: By understanding how these misbehaving antibodies cause brain swelling and change the connections between neurons, we can develop better medicines to restore normal brain function in patients.
Why you should care: Currently, there are no good treatments for this kind of immune disease that changes brain function. Through a better understanding of what happens to the neurons and their connections to each other during this process, we hope to develop a new and better treatment for people with this disease.
Encephalitis or brain inflammation can have various causes, including autoimmune disease. In this study, scientists look at a form of autoimmune encephalitis that targets specific proteins on neurons called NMDA receptors, which are important for memory, learning, and communication between neurons. They find that patients with this form of autoimmune encephalitis have antibodies that specifically target NMDA receptors, particularly in the hippocampus, a part of the brain that is best known for its role in short- and long-term memory. Targeted NMDA receptors are internalized by the neurons and are recycled or degraded. Since NMDA receptors are important for communication between neurons, reducing their numbers can change communication efficiency, and ultimately, brain function. The brain tries to compensate for these changes by modifying how the affected neurons are connected to other neurons. From this study, we have a better understanding of the disease mechanism of autoimmune encephalitis, and can develop better ways to treat patients with this, and similar, diseases.
In recent years, autoimmune encephalitides (believe it or not, this is a real word) have been found to attack synaptic proteins, affecting both signal transmission and synaptic function. In one type of encephalitis, the immune system targets synaptic NMDA receptors, which are necessary for glutamatergic transmission involved in plasticity, memory and learning. Patients suffering from this disorder exhibit behavioral and memory dysfunction. This study shows that patients with this form of encephalitis develop antibodies against the GluN1 subunit of NMDA receptors, present at a very high density in the hippocampus. Although the antibodies bind to an NMDA receptor region containing the ligand-binding domain, neurons treated with the antibodies do not exhibit electrophysiological changes before significant receptor internalization has occurred. Receptor hypofunction is primarily induced by internalization of NMDA receptors in both excitatory and inhibitory hippocampal neurons. The internalized NMDA receptors are trafficked to lysosomes and endosomes at an increasing rate over time, independently of receptor activity. Homeostatic regulation triggers changes in the inhibitory synaptic density of the hippocampus to partially compensate for the altered NMDA receptor activity, while gene transcription of the receptor remains unchanged. Ultimately, the findings here reveal molecular mechanisms that potentially underlie the behavioral and symptomatic changes experienced by patients with autoimmune encephalitis.