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The neural circuit mechanisms of anti-NMDA receptor encephalitis: revealing the role of NMDA receptors in spatial memory in mice

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Role of NMDA receptors in memory revealed

Following the discovery of anti-N-methyl D-aspartate receptor (anti-NMDAr) encephalitis, there has been a rapid increase in the number of patients diagnosed with this potentially fatal but treatable disease. Given the central role of NMDAr in learning and memory, memory deficits are among the main symptoms of this disorder.

Fundamental Research
Health

The EU-funded ISOLM project investigated NMDAr dysfunction in the hippocampus during memory formation and retrieval, using human antibodies from patients with anti-NMDAr encephalitis. One goal was to create accurate mouse behavioural models of long-term spatial memory impairments. Another was to quantify behaviourally the impact of anti-NMDAr infusion in the formation of new memories and the retrieval of existing ones. The activity of hippocampal place-cells across the behavioural experiment was also measured to determine the neural basis of memory deficits. Changes in the place field activity, which affect memory stability at the single-cell level, were also quantified. Scientists combined calcium imaging that utilised miniature microscopes with animal models, by redesigning the way osmotic pumps and mini-microscopes were implanted. The model could be used for different types of research that utilise pharmacology combined with calcium imaging in freely moving animal models. In addition, ISOLM developed a novel behavioural memory task to quantify the learning and retrieval of spatial memories. The entire task was controlled automatically by computer to allow several animals to be studied in parallel. The goal was to establish the behavioural experiment as a new standard for studying spatial navigation and retrieval in rodents. It also aimed to confirm that the behavioural task is susceptible in a controlled way to the pharmacological manipulation of the hippocampus as well as the immunoablation of the NMDA receptors. ISOLM work will help scientists to understand which type of memory component (formation and/or retrieval) is impaired by the effect of the NMDAr antibodies in patients. This could shed light on how best to treat patients after the acute phase of the disease, thereby reducing the long recovery period of 1-2 years. This will improve quality of life for patients and their families, as well as reduce the financial burden on public health services.

Keywords

NMDA receptors, memory, ISOLM, hippocampus, anti-NMDAr encephalitis

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