Long-term memory is a brain mechanism that allows us to encode and retain an almost unlimited amount of information throughout our lifetime. Key proteins that activate protein synthesis, such as the a subunit of the eIF2 initiation factor (eIF2a), are involved in the process.
In this study, published in the journal Nature and made in mice, researchers identified those neural circuits and connections by which, in both health and disease conditions, eIF2a impairs learning and memory when bound to a phosphorus molecule (phosphorylated), but enhances them in their non-phosphorylated form.
The research team, in which Albert Quintana and Elisenda Sanz participated under the coordination of McGill University (Montreal, Canada), showed that eIF2a is involved in the formation of new long duration memories through its activity in two types of neurons in the hippocampus: excitatory neurons and neurons expressing somatostatin, a group of inhibitory neurons.
In parallel and autonomously, the reduction of eIF2a phosphorylation in these two subpopulations is enough to increase protein synthesis, strengthen connections between neurons, and improve long-term memory.
“To study these effects, we used a technique we had developed, that showed that the changes in the excitatory neurons during learning are similar to those observed by genetically preventing eIF2a phosphorylation in these neurons”, explains Elisenda Sanz. This is important because it validated the genetic model and allowed identifying the changes that learning produces at a transcriptional level.
"The existence of two autonomous processes for memory consolidation mediated by the non-phosphorylated form of eIF2a may respond to an evolutionary advantage in ensuring and regulating the duration of a given memory", says Albert Quintana.
The study is the first to analyze separately the role of excitatory and inhibitory neurons in the hippocampus in the consolidation of these types of memories, and helps to understand the creation and maintenance of memories phenomenon, which continues to belargely unknown.
Original article: Sharma, V., Sood, R., Khlaifia, A. et al. eIF2α controls memory consolidation via excitatory and somatostatin neurons. Nature (2020). https://doi.org/10.1038/s41586-020-2805-8
Lesch-Nyhan is a rare genetical disease, affecting 1 in 380,000 newborns. Patients suffer from overproduction of uric acid, anemia, severe neurological problems, and compulsive self-injurious behavior. The pathology is caused by a deficiency of HGprt, an enzyme that participates in the metabolism of purine nucleotides. Purines regulate many biological processes and are part of the basic structure of DNA and RNA. They can be synthesized in two different metabolic pathways: the de novo synthesis, from simple precursors, such as amino acids and folic acid derivatives; and the salvage pathway, a recycling system where HGprt participates, in which the cell saves energy. A HGprt deficiency causes the acceleration of the de novo synthesis pathway to try to compensate the system.
Since measuring the nucleotide concentration in the brain of a living patient is not feasible, scientists often use cell cultures. However, the studies conducted until now in Lesch-Nyhan patients' cultured cells have never revealed any abnormalities in their nucleotide content. In this work, led by José Manuel López from the INC-UAB, and in collaboration with H. A. Jinnah from Emory University in Atlanta, and Rosa Torres from the Hospital Universitario La Paz in Madrid, the researchers show that these alterations could not be detected because, in most laboratories, cells are maintained in mediums that have extremely higher levels of folic acid than physiological concentrations.
"Culture mediums usually have 100 times more folic acid than the levels found in blood. This is for cells to divide and grow faster in a culture plate, but it does not reproduce what happens in the body", explains José Manuel López.
In this study, published in PNAS, researchers used physiological levels of folic acid in their culture mediums and observed two important alterations in patients’ fibroblasts. Firstly, an accumulation of ZMP, an intermediate product in the de novo nucleotide synthesis that is potentially toxic; and secondly, a reduction in ATP, the most abundant purine nucleotide in cells, which is essential for obtaining energy. Researchers also found ZMP derivatives increased in the urine and cerebrospinal fluid of patients, concluding that the alterations detected in fibroblasts can also occur in the brain and in other tissues.
"We present cell culture conditions that allow for the study of the mechanisms involved in the development of this disease. Our study also suggests a possible treatment, since the alterations observed in the cultures are reversed with high levels of folic acid”, indicates José Manuel López.
According to the researchers, the study may have highly relevant consequences, since manipulating folic acid levels can be a valuable strategy to study the pathogenesis of this rare disease, for which there is no known treatment. The discovery could also have implications in the research of other diseases in which high concentrations of folic acid in the culture medium could be masking cellular alterations, such as those in which nucleotide metabolism is affected.
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