HMN 2026: How Working memory may rely on calcium-tuned synaptic boosts

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 fiber 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 signaling (via the C2B domain of Munc13-1) and the calcium-calmodulin pathway (via a region that binds to this protein).

Analyzing the molecular sensors of the Munc13-1 protein

In animal models with these signaling pathways disrupted, the authors measured synaptic responses at mossy fiber 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 López-Murcia, a professor at the Department of Pathology and Experimental Therapeutics at the UB.

By identifying a specific molecular mechanism that links short-term synaptic strengthening to working memory performance, this study expands our understanding of how the brain rapidly stores and updates information.

“Disruption of the calcium-phospholipid signaling pathway increased the threshold for inducing post-tetanic potentiation and reduced its magnitude, suggesting that this pathway is particularly important for triggering strong short-term increases in synaptic transmission,” explains the researcher.

A maze of errors: When memory fails at the synapse

To study whether these synaptic alterations influence behavior, the team assessed the animal models in a spatial working memory task (an eight-arm radial maze). Mice carrying the Munc13-1 mutation—which disrupts calcium-mediated binding to cell membrane phospholipids—showed pronounced deficits consistent with impaired working memory, such as repeatedly returning to reward locations after having obtained the reward.

“These results provide experimental evidence that working memory may depend not only on sustained neuronal activation, but also on transient, activity-dependent changes in synaptic transmission that temporarily retain information within neural circuits,” says López-Murcia.

The study also highlights the role of the Munc13-1 protein as a key component that enables synapses to sustain to adapt in order to transfer and reinforce information during peaks of activity, an essential feature of neuronal activity in the hippocampus.

Previous studies have identified mutations in the human UNC13A gene that alter the sequence of multiple protein domains—including those examined in this study—in people with a wide range of neurological symptoms, notably intellectual disability. The findings of the new study highlight the crucial role of the Munc13-1 protein in healthy brain function and its clinical relevance in neurodevelopmental disorders.

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