Working memory is an essential cognitive function to develop day-to-day activities and temporarily retain information. It is a functional memory that allows us to understand information, learn and manage responses with control; capacities that are usually affected in some neurodegenerative diseases. Now, a study published in Cell Reports has identified a molecular pathway in the brain that is decisive for the correct functioning of working memory. Defects in this pathway could affect healthy brain function, underlining the importance of the proteins involved in it.
The study, developed in animal models, is led by Francisco José López-Murcia, principal investigator of the Cellular and molecular neurobiology group at IDIBELL and professor at the Faculty of Medicine and Health Sciences and the Institute of Neurosciences of the University of Barcelona (UBneuro). The team led by Professor Nils Brose, from the Max Planck Institute of Multidisciplinary Sciences (MPI-NAT, Gotinga, Germany), has also collaborated.
Preparation of synapses for neuronal transmission
Neurons communicate through contact points known as synapses, where information is transmitted by releasing neurotransmitters each time an electrical impulse arrives. This process is based on a very sophisticated and well-regulated set of proteins that ensures that the release of neurotransmitters occurs quickly and accurately.
Among them is Munc13-1, a key protein in the process in charge of preparing synaptic vesicles (the small sacs where neurotransmitters accumulate before release) for release. The research team led by Dr. Francisco José López Murcia has studied this protein, demonstrating that it must be regulated by calcium to correctly perform its function. As far as they have been able to verify, the regulation by calcium of Munc13-1 occurs through two complementary molecular pathways (the calcium-phospholipid pathway and calcium-calmodulin pathway). In certain brain regions, such as the hippocampus, the affectation of these pathways can impact on the correct functioning of working memory.
Calcium pathways, key to strengthening synapses and increasing effectiveness
To verify this, the researchers measured the synaptic responses, under normal conditions, of hippocampus synapses in animal models with these altered signalling pathways. “The results revealed that when Munc13-1 could not adequately detect calcium signals, synapses lost much of their ability to temporarily strengthen during repeated activity and therefore became less effective,” explains Dr. Francisco José López-Murcia.
This strengthening of synapses is vital. Neurons do not always communicate at a constant pace; they often work through brief bursts of activity that temporarily strengthen synapses and achieve a more efficient transmission of information. Therefore, “If this strengthening process fails, as it happens when calcium pathways are altered, not only does a functional impact occur at the cellular level, but some changes in behaviour can be observed” concludes the researcher.
A labyrinth of errors: when memory fails in synapses
To explore whether these synaptic alterations influence behavior, the team evaluated animal models in a spatial working memory task (an eight-arm radial maze). Mice with altered calcium pathways showed pronounced deficits consistent with a deterioration of working memory, such as repeatedly returning to reward sites after obtaining it.
“These results present experimental evidence to the idea that working memory can depend not only on sustained neuronal activation, but also on transient changes –dependent on activity – in synaptic transmission that temporarily retain information in neural circuits,” says López-Murcia.
With the discovery of a specific molecular mechanism that links short-term synaptic strengthening with working memory performance, this study broadens understanding of how the brain quickly stores and updates information.
The study also focuses on the role of the Munc13-1 protein as a central nucleus that facilitates the adaptation of synapses to sustain the transfer of information during peaks of activity and reinforce it, an essential characteristic of the neuronal activity of the hippocampus.
In previous studies, mutations in the human gene UNC13A (which codes for Munc13-1) have been identified that alter the sequence of multiple domains of the protein in people with a wide spectrum of neurological symptoms, among which intellectual disability stands out. The conclusions of the new study highlight the determining role of the Munc13-1 protein in healthy brain function and its clinical relevance in neurodevelopmental disorders.
The Bellvitge Biomedical Research Institute (IDIBELL) is a research center created in 2004 and specialized in cancer, neuroscience, translational medicine and regenerative medicine. It has a team of more than 1,500 professionals who, from 73 research groups, publish more than 1,400 scientific articles per year. IDIBELL is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L Hospitalet de Llobregat.
IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centres accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the HR Excellence in Research program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL is an Accredited Center of the AECC Scientific Foundation (FCAECC).