A team of scientists has made an important discovery about how the brain stores long-term memories. They identified the molecule KIBRA, which acts as a “glue” to anchor PKMζ, an enzyme critical for strengthening synaptic connections between neurons. This interaction ensures that memories are not lost as brain proteins degrade and regenerate, providing a deeper understanding of memory stability. The findings are published in Advances in science.
The scientists were prompted by a long-standing question in neuroscience: how can memories last for years or even decades when the molecules in our brains are constantly being replaced? Neurons store information in the strength of synapses, but the proteins and molecules in those synapses are unstable and degrade after just a few days. This creates a conundrum—if the building blocks of memory are so short-lived, what allows us to hold long-term memories?
The idea that certain molecular interactions can provide stability in memory storage has been around since 1984, when Francis Crick proposed that ongoing interactions between proteins could maintain synaptic strength over time. This new study sought to further explore this hypothesis, focusing on the role of PKMζ and how its interaction with another molecule, KIBRA, may contribute to long-term memory stability.
“I have been interested in memory since I was little. I also had the feeling that there were always deeper, simpler levels of understanding for any mysterious process, and I was driven by curiosity to find the deeper one about memory,” said study author Todd C. Sacktor, a SUNY distinguished professor. Downstate Health Sciences. the university.
Sacktor explained that in college, he became interested in understanding how memory is stored at the molecular level, focusing on the continuous strengthening of synapses during learning. During his neurology residency at Columbia, he worked in the laboratory of James Schwartz, who led him to the discovery of PKMζ, an enzyme that strengthens synaptic connections.
“The rest was just trying to understand what PKMζ did and how it worked,” Sacktor continued. “Ultimately, for the memory to last years, that is, beyond the lifetime of individual molecules, we realized that PKMζ had to have a partner, which is the discovery presented in this paper.”
André Fenton, a professor of neuroscience at New York University and another of the study’s principal investigators, added that he was drawn to this research because he was interested in uncovering the fundamental processes that underlie our subjective experience.
“While experience requires complex brain activity to process information, I have long thought that our concept of memory is central to this processing, not simply to store what has already happened, but also to generate expectations and beliefs. that influence, if not dictate, subsequent experience. Fenton said. “While it has always been a fascinating problem to figure out how memory can persist for years when the protein components last only days to weeks, work that challenged some of our previous findings and understanding pointed to a solution.”
To explore the link between KIBRA and PKMζ, the researchers used male laboratory mice. The scientists performed a series of experiments involving hippocampal slices, a brain region critical for memory, and various techniques such as proximity binding assays and confocal microscopy to visualize the molecular interactions between KIBRA and PKMζ.
They also used genetically modified mice lacking PKMζ to see how memory maintenance changed when this enzyme was missing. Additionally, behavioral tests, such as spatial memory tasks, were used to assess the impact of disruption of the KIBRA-PKMζ interaction on memory retention.
A key experiment involved applying a drug called ζ-stat, which blocks the interaction between KIBRA and PKMζ, to see if this would disrupt the stability of synaptic potentiation and long-term memory. Another experiment introduced a peptide called K-ZAP, which mimics the binding site of KIBRA and interferes with its ability to anchor PKMζ, further testing the importance of this interaction.
The study found evidence that KIBRA plays a vital role in stabilizing PKMζ at synapses, effectively creating a “persistent synaptic label” that helps maintain long-term memory. The researchers found that when synapses are activated during learning, KIBRA binds to those synapses and helps PKMζ stay connected. This connection ensures that synapses remain strong, even as other molecular components degrade and are replaced.
“For the first time, we have a basic biological understanding of how memory can last for years, perhaps even decades,” Sacktor told PsyPost.
More specifically, they observed that when ζ-stat was used to block the KIBRA-PKMζ interaction, it reversed the potentiation of synapses that had previously been strengthened during learning. This effect was selective, affecting only activated synapses that were involved in memory formation, leaving unactivated synapses unaffected. This indicates that the KIBRA-PKMζ interaction is crucial for maintaining the strength of memory-related synapses.
In behavioral tests, disruption of the KIBRA-PKMζ interaction in mice also led to a loss of long-term memory. Rats that received ζ-stat injections after learning a spatial memory task were unable to recall the location of a shock zone on subsequent tests. Interestingly, this effect was not seen in genetically modified mice lacking PKMζ, further confirming that the interaction of KIBRA with PKMζ is essential for memory maintenance.
The researchers also found that this molecular interaction is not only important for short-term memory, but can preserve memory for weeks. Even when PKMζ was degraded over time, KIBRA-PKMζ complexes remained at synapses, suggesting that new PKMζ molecules continue to be synthesized and incorporated at the same synaptic locations, allowing memories to persist long after initial learning.
“The ongoing KIBRA-PKMζ interaction explains how memory can last a lifetime, something people have been trying to understand for a very long time, at least since Plato wrote about it,” Fenton said.
“But there is more if we connect the dots. The human brain consists of about 100 billion neurons, each of which receives input synapses from about 10,000 other neurons. When we have an experience, we use the neural circuits of our brain to process information determined by the flow of electrochemical activity through subnetworks of those connections between millions of neurons. Memory can be the result of experience that changes those connections, usually a very small subset (1%). How does an experience today constantly change the connections so that the memory of the experience years ago?”
“Our work established that memory is the result of an active and ongoing biochemical process in which the kinase action of a persistently active catalytic protein, PKMζ is targeted at experience-activated connections within neurons that make up information processing connections of experience. mediating neural circuitry,” Fenton explained. “PKMζ is generated in an activated neuron, and because KIBRA, a targeting molecule, accumulates at the activated junctions, it directs the kinase action of PKMζ at those specific sites.
“The KIBRA-PKMζ interaction persists because the KIBRA-PKMζ complex is more stable than the individual protein components, and like the paradox of the ship of Theseus that persists despite replacement of all the planks, the KIBRA-PKMζ complex persists even though the individual protein components are replaced constantly.”
“The key point is that experience activates the neural circuits that process information, and that processing creates memory, which depends on an elegant, constantly active biophysical process that immediately stores the information and, by storing that information, also changes the neural circuitry and with it the processing of information. information inside. what experience will happen in the future,” Fenton told PsyPost. “Memory is about the future.”
Although the study provides strong evidence that KIBRA is essential for long-term memory retention by stabilizing PKMζ at synapses, certain limitations remain. Researchers acknowledge that not all forms of memory can rely on this molecular interaction. For example, the study found that some types of memory, such as contextual fear memory, are retained through PKMζ-independent mechanisms. Understanding how these different systems work will require further investigation.
“There are some memories that are not preserved by PKMζ,” Sacktor noted. “Does KIBRA play a role in these by interacting with a different but related molecule in strengthening synapses, or are there entirely different mechanisms?”
Another limitation is that while KIBRA helps explain how memories can last for years, regardless of molecular turnover, the study did not fully explain how the process of memory formation begins—specifically, how KIBRA is initially recruited to the synapses involved. in the formation of memory. This will be an important area for future research.
The researchers also plan to explore potential applications of their findings for the treatment of memory-related disorders. Since the KIBRA-PKMζ interaction is so critical to memory stability, drugs targeting this process could potentially be used to improve memory in conditions such as Alzheimer’s disease or weaken harmful memories in conditions such as post-traumatic stress disorder.
“We want to explain how the process of memory persistence starts,” Fenton said. “In other words, how does KIBRA appear and accumulate; how memory-altered connections are arranged within a neuron and between neurons; how does the change mediated by KIBRA-PKMζ change in relation to information processing; and how can this basic neurobiology be used to improve outcomes in disorders such as Alzheimer’s disease and mental illness?”
“With every fundamental discovery in biology, there will be ‘low-hanging fruit’ in medicine—diseases that can now be treated,” Sacktor said. “Often diseases cannot be predicted ahead of time. I am curious what psychiatric or neurological diseases will be for the discovery of the role of KIBRA-PKMζ in memory.”
“Doing this work is very slow and careful, and sometimes frustrating, but it’s always been a joy!” added Fenton.
The study, “KIBRA anchoring PKMζ action preserves memory persistence,” was authored by Panayiotis Tsokas, Changchi Hsieh, Rafael E. Flores-Obando, Matteo Bernabo, Andrew Tcherepanov, A. Iván Hernández, Christian Thomas, Peter J. Bergold, James E. Cottrell, Joachim Kremerskothen, Harel Z. Shouval, Karim Nader, André A. Fenton, and Todd C. Sacktor.