A recent study conducted by an international team of researchers has shed light on the biological mechanisms that underlie the formation and retention of long-term memories. At the heart of this discovery is the identification of a molecule called KIBRA, which acts as a crucial “glue” that binds together other molecules, thereby strengthening the formation of memories.
From cherished childhood memories to important life events, our ability to retain memories for a lifetime has long puzzled scientists. But how exactly do these memories endure for decades?
Published in the journal Science Advances, this study marks a significant breakthrough in our understanding of long-term memory storage. Previous research has focused on the individual functions of single molecules in memory storage, but this study reveals how these molecules work collaboratively to ensure the persistence of memories.
André Fenton, a professor at New York University, one of the lead researchers of the study, explains, “Our study demonstrates how molecules work in concert to facilitate lasting memory storage instead of acting in isolation.”
Todd Sacktor, another principal investigator from SUNY Downstate Health Sciences University, emphasizes the importance of comprehending memory retention mechanisms in guiding future research on memory-related disorders.
It is widely known that memories are stored in neurons through a combination of strong and weak synapses, which dictate the connectivity and functionality of neural networks. However, the molecules involved in synapses are dynamic, constantly moving within neurons and undergoing turnover in a matter of hours to days. This poses a fundamental question: How do memories remain stable over years or even decades?
The researchers conducted experiments on laboratory mice to investigate the role of KIBRA, a protein associated with human genetic variations linked to both strong and weak memory. They focused on its interactions with another critical molecule in memory formation, Protein Kinase Mzeta (PKMzeta), known for enhancing synapse strength in mammals but susceptible to degradation after a few days.
Their findings revealed that KIBRA acts as a “persistent synaptic tag,” binding to strong synapses and PKMzeta while avoiding weak synapses, thereby serving as the missing link in maintaining long-term memories.
Sacktor explains, “KIBRA gets selectively positioned in the synapses involved in memory formation, where it attracts PKMzeta to reinforce those synapses. This creates a cycle where the synapses adhere to newly formed KIBRA, attracting additional PKMzeta.”
The study showcased in Science Advances demonstrated that disrupting the KIBRA-PKMzeta bond leads to the erasure of old memories. Prior research had shown that increasing PKMzeta in the brain could enhance weak memories, a phenomenon previously puzzling. However, the concept of persistent synaptic tagging by KIBRA offers an explanation for this memory enhancement by focusing on specific sites tagged by KIBRA.
Fenton notes, “The discovery of the persistent synaptic tagging mechanism sheds light on clinically relevant aspects of memory-related neurological and psychiatric disorders.”
The researchers draw parallels between their findings and a concept introduced by Francis Crick in 1984, likening memory storage to Theseus’s Ship, a philosophical argument from Greek mythology. In this analogy, new components replace old ones to preserve the ship over time.
“Our discovery of the persistent synaptic tagging mechanism mirrors how new components sustain Theseus’s Ship over generations, enabling memories to endure even as the proteins responsible for memory maintenance are refreshed,” says Sacktor. “While Francis Crick theorized this concept decades ago, it took forty years to identify KIBRA and PKMzeta as the key components and elucidate their interactive mechanism.”
The study involved researchers from McGill University in Canada, University Hospital of Münster in Germany, and University of Texas Medical School at Houston.
This research received support from various funding sources including the National Institutes of Health, Natural Sciences and Engineering Research Council of Canada, and the Garry and Sarah S. Sklar Fund.
