Working memory is a cognitive function that is essential for carrying out everyday activities and temporarily retaining information. This process enables us to understand information, learn and manage responses in a controlled manner - abilities that are often impaired in certain neurodegenerative diseases. Now, a study published in Cell Reports has identified a molecular pathway in the brain that is crucial for the proper functioning of working memory.
The study, conducted using animal models, is led by Francisco José López-Murcia, a professor at the Faculty of Medicine and Health Sciences and the Institute of Neurosciences of the University of Barcelona (UBneuro), and a member of the Bellvitge Biomedical Research Institute (IDIBELL). The team led by Professor Nils Brose at the Max Planck Institute for Multidisciplinary Sciences (MPI-NAT, Göttingen, Germany) is also participating in the project.
How synapses prepare for neural transmission
Neurons do not always communicate at a constant rate. In many neural circuits, brief bursts of activity occur that temporarily strengthen synapses, allowing for more efficient transmission of information. Two such transient strengthening processes are short-term facilitation and post-tetanic potentiation (PTP), both of which are particularly prominent at mossy fibre synapses, which are thought to contribute to working memory.
At the molecular level, the team focused on studying the Munc13-1 protein, a key factor that prepares synaptic vesicles for the release of neurotransmitters, a process known as vesicular priming. The study demonstrates that Munc13-1 must be regulated by calcium via two complementary pathways: calcium-phospholipid signalling (via the C2B domain of Munc13-1) and the calcium-calmodulin pathway (via a region that binds to this protein).
Analysing the molecular sensors of the Munc13-1 protein
In animal models with these signalling pathways disrupted, the authors measured synaptic responses at mossy fibre synapses in the hippocampus during stimulation patterns that mimic physiological activity.
"The results show that when Munc13-1 was unable to detect calcium signals properly, the synapses lost much of their ability to temporarily strengthen during repeated activity," says Francisco José López-Murcia, a professor at the Department of Pathology and Experimental Therapeutics at the UB.
