A team of researchers has made a groundbreaking discovery in understanding how the brain stores long-term memories. They identified a molecule known as KIBRA, which acts as a stabilizer for PKMζ, an enzyme that plays a crucial role in strengthening synaptic connections. This molecular interaction preserves memories, even as brain proteins continuously degrade and regenerate, shedding new light on the stability of memory over time. The findings were published in Science Advances.
The scientists were driven by a fundamental question in neuroscience: how can memories last for years or even decades when the brain’s proteins, including those involved in synapses, are replaced within days? Neurons encode information in the strength of their synapses, yet these synaptic components are not stable. The puzzle has long been: if the molecular building blocks of memory degrade quickly, what mechanism allows for the retention of long-term memories?
This concept was first proposed in 1984 by Francis Crick, who hypothesized that certain molecular interactions could provide the stability necessary for memories to endure. In this new study, the researchers focused on the enzyme PKMζ and its interaction with KIBRA, which seems to play a vital role in ensuring memory persistence.
“I have been fascinated by memory since childhood, always seeking a deeper understanding of the processes behind it,” said study lead author Todd C. Sacktor, a distinguished professor at SUNY Downstate Health Sciences University. Sacktor became interested in memory storage at the molecular level during his college years, particularly the mechanisms that strengthen synapses during learning. This passion ultimately led him to the discovery of PKMζ and, through years of research, to uncovering its connection to KIBRA.
Another principal investigator, André Fenton, a professor of neural science at New York University, was drawn to the study by his interest in how memory shapes our perception of experience. “Memory isn’t just about recording what happened; it generates expectations that influence future experiences,” Fenton explained. He has long been intrigued by how memory can persist for years when its protein components are short-lived.
To investigate the role of KIBRA and PKMζ in memory stability, the researchers used male laboratory mice. They conducted various experiments, including tests on hippocampal brain slices—an area critical for memory—and employed techniques like proximity ligation assays and confocal microscopy to visualize molecular interactions. By using genetically modified mice lacking PKMζ, they were able to study the effects of disrupting this enzyme on memory retention.
One experiment involved administering a drug called ζ-stat, which blocks the KIBRA-PKMζ interaction. This treatment disrupted the stability of synapses that had been strengthened through learning, leading to a loss of memory in the mice. Another experiment introduced a peptide, K-ZAP, which interfered with KIBRA’s ability to anchor PKMζ. Both approaches demonstrated that the KIBRA-PKMζ bond is crucial for maintaining the strength of synaptic connections linked to long-term memory.
Sacktor explained that the KIBRA-PKMζ interaction essentially creates a “persistent synaptic tag,” stabilizing the synapse even as individual proteins degrade. The study showed that KIBRA binds to activated synapses during learning, ensuring PKMζ stays in place, which prevents memory loss. This mechanism may explain how memories can last for years or even decades, despite the rapid turnover of synaptic proteins.
Importantly, the researchers found that disrupting this molecular interaction specifically affected synapses involved in memory formation while leaving unactivated synapses unaffected. Behavioural tests revealed that mice treated with ζ-stat after learning a spatial memory task could no longer remember the location of a shock zone, whereas untreated mice retained the memory.
Interestingly, even when PKMζ degraded over time, the KIBRA-PKMζ complexes persisted at the synapses, indicating that new PKMζ molecules are continually synthesized and anchored in the same locations. This discovery suggests that KIBRA helps to ensure the ongoing stability of memories by facilitating the renewal of essential components at the synapse.
“For the first time, we have a fundamental understanding of how memory can endure for years, or even a lifetime,” Sacktor noted. The researchers believe this molecular mechanism might explain the persistence of memories over extended periods, much like the paradox of Theseus’ ship, where individual parts are replaced but the structure remains intact.
Fenton expanded on this idea by discussing how memory shapes future experiences. “When we form a memory, it alters the connections in the brain that process information, and those changes influence how future experiences are interpreted and remembered,” he said. Memory, in essence, is an active, ongoing process that continuously shapes the brain’s circuitry.
Despite the breakthrough, the researchers acknowledge limitations in their findings. Not all forms of memory depend on PKMζ, as the study revealed that certain types of memories, such as contextual fear memory, are maintained through alternative mechanisms. Future studies will need to explore whether KIBRA interacts with other molecules to preserve these memories or if different processes are involved altogether.
The researchers also aim to investigate how KIBRA is initially recruited to synapses during memory formation, as this remains an open question. Understanding how this process begins will be key to further unravelling the complexities of memory persistence.
Looking ahead, the team hopes their findings could have clinical applications. Since the KIBRA-PKMζ interaction is essential for memory retention, targeting this process with drugs could lead to new treatments for memory-related conditions like Alzheimer’s disease. Conversely, weakening this interaction might offer therapeutic avenues for disorders such as post-traumatic stress disorder (PTSD), where diminishing traumatic memories could be beneficial.
As Sacktor explained, “Fundamental discoveries in biology often lead to unexpected medical applications. We are curious to see which neurological or psychiatric disorders may be impacted by our understanding of KIBRA’s role in memory.”
Although the research has been a long and meticulous process, Fenton described it as an exciting and joyous journey. The study, titled “KIBRA anchoring the action of PKMζ maintains the persistence of memory,” was authored by Panayiotis Tsokas, Changchi Hsieh, Rafael E. Flores-Obando, Matteo Bernabo, and other researchers from institutions including SUNY Downstate and New York University.
