New research uncovers the crucial role of the KIBRA protein in maintaining memories for decades, offering insights into potential treatments for memory-related disorders.
A groundbreaking study published in Science Advances [1] has shed light on the molecular mechanisms underpinning long-term memory formation and retention. An international team of researchers has identified a key molecule, KIBRA (kidney and brain expressed protein), which acts as a ‘glue’ to solidify memory formation at the synaptic level. This discovery provides a biological explanation for how memories can persist for a lifetime, potentially paving the way for new approaches to address memory-related conditions.
The paradox of stable memories
For years, neuroscientists have grappled with a fundamental paradox: how can memories remain stable for decades when the molecular components of synapses are in constant flux? It has long been established that neurons store information as patterns of strong and weak synaptic connections, determining the function of neural networks. However, the molecules within synapses are notoriously unstable, continuously moving and being replaced within hours or days.
This study, led by researchers from New York University and SUNY Downstate Health Sciences University, provides a compelling answer to this conundrum. Professor André Fenton of New York University, one of the study’s principal investigators, explains: “Previous efforts to understand how molecules store long-term memory focused on the individual actions of single molecules. Our study shows how they work together to ensure perpetual memory storage.”
The role of KIBRA
Using laboratory mice, the researchers focused on KIBRA, a protein whose human genetic variants have been associated with both enhanced and impaired memory function. They investigated KIBRA’s interactions with another crucial molecule in memory formation, protein kinase Mzeta (PKMzeta), an enzyme known to strengthen mammalian synapses, but which degrades after a few days.
The experiments revealed that KIBRA serves as a ‘persistent synaptic tag’, selectively positioning itself in activated synapses during memory formation. This molecular tag then attracts and binds to PKMzeta, maintaining the strength of these specific synapses over time.
Professor Todd Sacktor of SUNY Downstate Health Sciences University, another principal investigator, elaborates: “PKMzeta then attaches to the KIBRA-synaptic-tag and keeps those synapses strong. This allows the synapses to stick to newly made KIBRA, attracting more newly made PKMzeta.”
Implications for memory disorders
This newly discovered mechanism has significant implications for understanding and potentially treating memory-related disorders. The researchers demonstrated that disrupting the KIBRA-PKMzeta bond can erase old memories, while increasing PKMzeta in the brain can enhance weak or faded memories by acting at KIBRA-tagged sites.
“The persistent synaptic tagging mechanism for the first time explains these results that are clinically relevant to neurological and psychiatric disorders of memory,” notes Prof. Fenton.
A modern realisation of an ancient concept
Intriguingly, this research affirms a concept introduced in 1984 by Francis Crick, drawing parallels with the philosophical paradox of Theseus’s Ship. This ancient Greek thought experiment questions whether an object that has had all its parts replaced remains the same object.
Prof. Sacktor explains: “The persistent synaptic tagging mechanism we found is analogous to how new planks replace old planks to maintain Theseus’s Ship for generations and allows memories to last for years even as the proteins maintaining the memory are replaced.”
This study marks a significant advance in our understanding of the molecular basis of long-term memory. As Prof. Fenton notes: “A firmer understanding of how we keep our memories will help guide efforts to illuminate and address memory-related afflictions in the future.”
Reference:
1. Fenton, A. A., Sacktor, T. C., et al. (2024). KIBRA anchoring the action of PKM maintains the persistence of memory.
Science Advances. 26 June 2024. https://doi.org/10.1126/sciadv.adl0030
