A study published in Cell Reports identifies a molecular pathway in the brain that is essential for the proper functioning of working memory, according to a statement released on Mar. 17. The research was led by Francisco José López-Murcia from the University of Barcelona and included collaboration with Nils Brose's team at the Max Planck Institute for Multidisciplinary Sciences.
Working memory allows people to temporarily retain and manage information, which is necessary for learning and daily activities. This function is often impaired in neurodegenerative diseases, making its underlying mechanisms important to understand.
The researchers used animal models to examine how neurons communicate through synapses, focusing on two processes—short-term facilitation and post-tetanic potentiation—that strengthen synaptic connections during bursts of activity. They studied the Munc13-1 protein, which prepares synaptic vesicles for neurotransmitter release. The study found that Munc13-1 must be regulated by calcium through two pathways: calcium-phospholipid signaling and the calcium-calmodulin pathway.
"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," said Francisco José López-Murcia. He added, "Disruption of the calcium-phospholipid signalling 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."
To test if these changes affected behavior, mice with mutations disrupting Munc13-1’s calcium-mediated binding showed deficits in spatial working memory tasks. "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," said López-Murcia.
The findings highlight Munc13-1 as a key component enabling synapses to adapt during peaks of activity—a feature critical for hippocampal function. Previous studies have linked mutations in related genes to neurological symptoms such as intellectual disability, underlining the clinical relevance of this research.
