Summary: A new study reveals the role of the molecule KIBRA in the formation of long-term memories. The researchers found that KIBRA acts as a “glue”, binding to the enzyme PKMzeta to strengthen and stabilize synapses, crucial for memory storage.
This discovery could lead to new treatments for memory-related conditions. The findings confirm a long-held hypothesis about memory storage mechanisms.
Key facts:
- The role of KIBRA: Acts as a molecular “glue” for the formation of long-term memory.
- Memory stabilization: KIBRA binds to PKMzeta to strengthen synapses.
- Clinical potential: May inform treatments for memory-related disorders.
Source: NYU
Whether it’s visiting a zoo for the first time or learning to ride a bike, we have childhood memories that carry over into adulthood. But what does it explain? HOW these memories last almost a lifetime?
A new study in the journal Advances in science, conducted by an international team of researchers, has discovered a biological explanation for long-term memories. It focuses on discovering the role of one molecule, KIBRA, that serves as a “glue” for other molecules, thereby strengthening memory formation.
“Previous efforts to understand how molecules store long-term memory focused on the individual actions of single molecules,” explains André Fenton, a professor of neural science at New York University and one of the study’s principal investigators.
“Our study shows how they work together to ensure permanent memory storage.”
“A stronger understanding of how we store our memories will help guide future efforts to illuminate and treat memory-related suffering,” adds Todd Sacktor, a professor at SUNY Downstate University Health Sciences and a by the study’s principal investigators.
It has long been established that neurons store information in memory as a pattern of strong synapses and weak synapses, which determines the connectivity and function of neural networks.
However, molecules in synapses are unstable, constantly moving in neurons, and being worn out and replaced by hours to days, thus raising the question: how, then, can memories last for years to decades?
In a study using laboratory mice, the scientists focused on the role of KIBRA, or the protein expressed by the kidneys and brain, whose human genetic variants are associated with good and poor memory.
They focused on KIBRA’s interactions with other molecules essential for memory formation—in this case, the protein kinase Mzeta (PKMzeta). This enzyme is the most important molecule for strengthening normal mammalian synapses known, but it degrades after a few days.
Their experiments reveal that KIBRA is the “missing link” in long-term memories, serving as a “persistent synaptic label,” or glue, that sticks to strong synapses and PKMzeta, while also avoiding weak synapses.
“During memory formation, the synapses involved in the formation are activated—and KIBRA is selectively positioned at these synapses,” explains Sacktor, a professor of physiology, pharmacology, anesthesiology and neurology at SUNY Downstate.
“PKMzeta then attaches to the synaptic tag KIBRA and keeps those synapses strong. This allows synapses to attach to newly formed KIBRAs, attracting more newly formed PKMzetas.”
More specifically, their experiments in Advances in science the letters show that breaking the KIBRA-PKMzeta connection erases the old memory. Previous work had shown that random increases in PKMZeta in the brain INCREASES weak or faded memories, which was mysterious because it should have done the opposite by acting at random sites, but persistent synaptic labeling by KIBRA explains why additional PKMzeta was improving memory, acting only at KIBRA-labeled sites.
“The persistent mechanism of synaptic labeling for the first time explains these results that are clinically relevant to neurological and psychiatric disorders of memory,” notes Fenton, who is also on the faculty at NYU Langone Medical Center’s Neuroscience Institute.
The paper’s authors note that the research affirms a concept introduced in 1984 by Francis Crick. Sacktor and Fenton point out that his proposed hypothesis to explain the brain’s role in maintaining memory despite ongoing cellular and molecular changes is a Ship of Theseus mechanism—borrowed from a philosophical argument originating in Greek mythology in which the planks of new ones replace the old ones to preserve the Ship of Theseus for years.
“The persistent synaptic tagging mechanism we found is analogous to how new boards replace old boards to preserve the Ship of Theseus over generations, and allows memories to last for years even when the proteins that store the memory are replaced,” says Sacktor.
“Franciscus Crick intuited the mechanism of Theseus’ shuttle, even anticipating the role of a protein kinase. But it took 40 years to discover that the components are KIBRA and PKMzeta and to work out the mechanism of their interaction.”
The study also involved researchers from Canada’s McGill University, Germany’s University Hospital Münster and the University of Texas Medical School at Houston.
Funding: This work was supported by grants from the National Institutes of Health (R37 MH057068, R01 MH115304, R01 NS105472, R01 MH132204, R01 NS108190), the Natural Sciences and Engineering Research Council of Canada Discovery23 and Garh5 (20) and the S. Sklar Fund.
About this news about genetics and memory research
Author: James Devitt
Source: NYU
Contact: James Devitt – NYU
Image: Image is credited to Neuroscience News
Original research: Open access.
“KIBRA anchoring PKMζ action maintains memory persistence” by André Fenton et al. Advances in science
ABSTRACT
KIBRA anchoring action of PKMζ preserves memory persistence
How can short-lived molecules selectively maintain the potentiation of activated synapses to maintain long-term memory?
Here, we find adapter protein expressed by kidney and brain (KIBRA), a postsynaptic scaffolding protein genetically linked to human memory performance, complex with protein kinase Mzeta (PKMζ), anchoring the potentiating action of the kinase to maintain long-term potentiation of late phase (late -LTP) in activated synapses.
Two structurally different antagonists of KIBRA-PKMζ dimerization disrupt established late and long-term spatial memory, but neither measurably affects basal synaptic transmission.
Neither antagonist affects PKMζ-independent LTP or memory that is preserved by compensating PKCs in ζ-knockout mice; thus, both agents require PKMζ for their effect. KIBRA-PKMζ complexes retain 1-month memory regardless of PKMζ turnover.
Therefore, it is not PKMζ alone, nor KIBRA alone, but the ongoing interaction between the two that maintains late and long-term memory.