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Anti-NMDA receptor encephalitis, a form of autoimmune encephalitis, is a neuro-psychiatric disorder that can cause memory loss, cognitive and behavioural disturbances, abnormal movements, seizures, coma and death. It occurs when antibodies produced by the body’s own immune system attack proteins called NMDA receptors that control electrical impulses in the brain.
Though the underlying cause of anti-NMDAr encephalitis remains unclear, the EU-funded ISOLM project has led to promising insights into how its effects can be reduced and treatments improved to hasten a patient’s recovery. The initiative was co-supervised by Jaime de la Rocha and Josep Dalmau, who discovered, characterised and named anti-NMDAr encephalitis in 2007.
“The double challenge addressed in ISOLM was to understand how memories are formed and recalled in the hippocampus region of the brain and how this process is affected in anti-NMDAr encephalitis,” says Pablo Jercog, the lead investigator on the project, which was coordinated by the Institut d'investigacions Biomèdiques August Pi i Sunyer in Spain. “The ultimate goal is to enable treatments that speed up the recovery process of patients with highly reduced cognitive functions, enabling them to go back to their normal lives and thereby reducing the economic and social burden of the disease.”
Most people diagnosed with anti-NMDAr encephalitis, around 40 % of whom are children, respond well to current immunosuppressive treatments. But it can take as long as two years for them to recover and return to work or school.
Mice provide key human memory clues
The ISOLM team conducted innovative experiments with mice navigating mazes in search of food rewards. This spatial navigation task forms part of a unique rodent behavioural model that can be compared with human patients undergoing memory tests.
The experiments, designed with the input of medical doctors, electrophysiologists, physicists and bioengineers, could also serve as a new paradigm for spatial navigation in rodents and become a reference for other researchers studying the effects of neuro-autoimmune diseases affecting important cognitive processes.
“We have been able to record the neural activity of NMDA receptors while injecting antibodies directly into the brains of the mice recalling spatial memories and creating new ones. This novel approach allows us to interrupt the most important molecular mechanisms of memory formation, without affecting other behavioural aspects of the animal’s conduct,” Jercog says.
By recording and analysing the activity of an unprecedented number of neurons simultaneously, the ISOLM researchers are starting to decipher how memories are written, erased and recovered during different phases of the experimental model of the disease. This model imitates the phases of anti-NMDAr encephalitis in humans, including the long recovery period.
“The results will allow us to start testing treatments involving cognitive training and drugs that accelerate the process of recovering from the dysfunction caused by the disease,” Jercog says. “This would substantially improve quality of life of patients and their families, as well as reduce the cost of healthcare.”