Summary: A new study reveals the role of the molecule KIBRA in the formation of long-term memories. The researchers discovered that KIBRA acts as a “glue” by binding to the PKMzeta enzyme to strengthen and stabilize synapses, which are critical for memory retention.
This finding could lead to new treatments for memory-related conditions. The findings confirm a long-standing hypothesis about memory storage mechanisms.
Key facts:
- The role of KIBRA: Acts as a molecular “glue” to form long-term memory.
- Memory stabilization: KIBRA binds to PKMzeta to strengthen synapses.
- Clinical potential: May provide information on treatment of memory disorders.
source: NYU
Whether it’s our first visit to the zoo or when we learned to ride a bike, we have childhood memories that carry over into adulthood. But what does it explain how those memories last almost a lifetime?
A new study in the journal Scientific progress, conducted by a team of international researchers, revealed a biological explanation for long-term memories. It focused on discovering the role of a molecule, KIBRA, that serves as a “glue” for other molecules, thereby solidifying memory formation.
“Previous efforts to understand how molecules store long-term memory have focused on the individual actions of single molecules,” explains Andre Fenton, professor of neuroscience at New York University and one of the study’s principal investigators.
“Our study shows how they work together to provide persistent memory storage.”
“A better understanding of how we store our memories will help guide efforts to illuminate and address memory-related problems in the future,” adds Todd Sactor, professor at SUNY Downstate Health Sciences University and one of 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.
Molecules at synapses, however, are unstable, constantly moving within neurons and worn and replaced over hours to days, thus raising the question: How then can memories be stable for years to decades?
In a study using laboratory mice, the scientists focused on the role of KIBRA, a protein expressed in the kidney and brain whose human genetic variants are associated with both good and poor memory.
They focused on KIBRA’s interactions with other molecules that are critical to memory formation—in this case, protein kinase Mzeta (PKMzeta). This enzyme is the most important molecule for strengthening normal mammalian synapses known, but it breaks down after a few days.
Their experiments revealed that KIBRA is the “missing link” in long-term memories, serving as a “permanent synaptic label” or glue that sticks to strong synapses and to PKMzeta while avoiding weak synapses.
“During memory formation, the synapses involved in the formation are activated — and KIBRA selectively positions itself at those synapses,” explains Sactor, professor of physiology, pharmacology, anesthesiology and neurology at SUNY Downstate.
“PKMzeta then attaches to the KIBRA-synaptic-tag and keeps those synapses healthy. This allows the synapses to adhere to the newly formed KIBRA, attracting more newly formed PKMzeta.
Specifically, their experiments in Scientific progress paper show that breakage the KIBRA-PKMzeta connection deletes the old memory. Previous work has shown that a random increase in PKMzeta in the brain improves weak or faded memories, which was mysterious because it should have done the opposite by acting on random sites, but the persistent synaptic labeling by KIBRA explained why the extra PKMzeta improved memory by acting only on the KIBRA-labeled sites.
“A persistent synaptic tagging mechanism explains for the first time these results, which are clinically relevant to neurological and psychiatric memory disorders,” notes Fenton, who is also on the faculty at NYU Langone Medical Center’s Neuroscience Institute.
The authors of the paper note that the study confirms a concept introduced in 1984 by Francis Crick. Sactor and Fenton point out that his proposed hypothesis to explain the brain’s role in memory storage despite constant cellular and molecular changes is a Ship of Theseus mechanism—borrowed from a philosophical argument derived from Greek mythology in which new planks replace old, to sustain Theseus’s ship for years.
“The persistent synaptic tagging mechanism we discovered is analogous to the way new planks replace old planks to sustain the Ship of Theseus for generations, and allows memories to persist for years, even as memory-supporting proteins are replaced.” , says Sactor.
“Francis Crick sensed this mechanism on the ship of Theseus, even predicting the role of protein kinase. But it took 40 years to discover that the components were 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.
Financing: 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 Discovery (203523), and Garry and Sarah S. Sklar Fund.
About this news about genetics and memory research
Author: James Devitt
source: NYU
Contact: James Devitt – New York University
Image: Image credit: Neuroscience News
Original Research: Free access.
“KIBRA anchoring PKMζ action maintains memory persistence” by André Fenton et al. Scientific progress
Summary
KIBRA anchors PKMζ action maintains memory persistence
How can short-term molecules selectively maintain the potentiation of activated synapses to support long-term memory?
Here we find kidney and brain expressed adapter protein (KIBRA), a postsynaptic scaffolding protein genetically related to human memory performance, complexes with protein kinase Mzeta (PKMζ) anchoring the potentiating action of the kinase to maintain a late phase of long-term potentiation (late -LTP) at activated synapses.
Two structurally different antagonists of KIBRA-PKMζ dimerization impaired established late LTP and long-term spatial memory, but neither measurably affected basal synaptic transmission.
Neither antagonist affected PKMζ-independent LTP or memory, which are maintained by compensating PKCs in ζ-knockout mice; thus, both agents require PKMζ for their effect. KIBRA-PKMζ complexes maintain 1-month memory despite PKMζ turnover.
Therefore, not PKMζ alone, nor KIBRA alone, but a continuous interaction between the two supports late LTP and long-term memory.
