Memories “Stick” Thanks to Two-Molecule Synaptic Tagging Mechanism

A new murine study headed by a team at New York University has uncovered a biological explanation for our ability to retain memories over the long term. The discovery centers on the role of a molecule, KIBRA, that serves as a “glue” to other molecules, thereby solidifying memory formation.

“Previous efforts to understand how molecules store long-term memory focused on the individual actions of single molecules,” noted 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 perpetual memory storage.” Co-principal investigator Todd Sacktor, PhD, a professor at SUNY Downstate Health Sciences University, added, “A firmer understanding of how we keep our memories will help guide efforts to illuminate and address memory-related afflictions in the future.” Fenton, Sacktor, and an international research team reported on their findings in Nature Medicine, in a paper titled “KIBRA anchoring the action of PKMζ maintains the persistence of memory.”

In their report the researchers concluded, “Here, we find kidney and brain expressed adaptor protein (KIBRA), a postsynaptic scaffolding protein genetically linked to human memory performance, complexes with protein kinase Mzeta (PKMζ), anchoring the kinase’s potentiating action to maintain late-phase long-term potentiation (late-LTP) at activated synapses.”

Whether it’s a first-time visit to a zoo or when we learned to ride a bicycle, we have memories from our childhoods kept well into adult years. But what explains how these memories last nearly an entire lifetime? “How molecules lasting only hours to days can maintain memory that persists weeks to years is a long-standing fundamental question in neuroscience,” the authors pointed out.

It’s been long-established that neurons store information in memory as the pattern of strong synapses and weak synapses, which determines the connectivity and function of neural networks. However, the molecules in synapses are unstable, continually moving around in the neurons, and wearing out and being replaced in hours to days. “How can short-lived molecules selectively maintain the potentiation of activated synapses to sustain long-term memory?” the team asked in their paper.

In a study using laboratory mice, the scientists focused on the role of kidney and brain expressed protein (KIBRA), the human genetic variants of which are associated with both good and poor memory. They focused on KIBRA’s interactions with other molecules crucial to memory formation, and one known as protein kinase Mzeta (PKMzeta; PKMζ). This enzyme is the most crucial molecule known for strengthening normal mammalian synapses, but it degrades after a few days.

The newly reported experiments revealed that KIBRA is effectively the missing link in long-term memories, serving as a persistent synaptic tag, or glue, that sticks to strong synapses and to PKMζ while also avoiding weak synapses.

“During memory formation the synapses involved in the formation are activated—and KIBRA is selectively positioned in these synapses,” explains Sacktor, a professor of physiology, pharmacology, anesthesiology, and neurology at SUNY Downstate. “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.”

More specifically, their work showed that breaking the KIBRA-PKMzeta bond erases old memory. Previous work had shown that randomly increasing PKMzeta in the brain enhances weak or faded memories, which was unexpected because it should have done the opposite by acting at random locations, but the persistent synaptic tagging by KIBRA explains why the additional PKMζ was memory enhancing, by only acting at the KIBRA tagged sites. “Our results reveal that coupling of PKMζ and KIBRA is necessary for long-term memory maintenance …” the scientists reported. “Thus, it is not PKMζ alone, nor KIBRA alone, but the interaction between the two that maintains LTP and memory.”

The paper’s authors noted that the research affirms a concept introduced in 1984 by Francis Crick. “In 1984, Crick proposed that the continual interaction between synaptic proteins maintains the strengthening of synapses in the face of molecular turnover,” they wrote.

Sacktor and Fenton commented that his proposed hypothesis to explain the brain’s role in memory storage despite constant cellular and molecular changes is a Theseus’s Ship mechanism—borrowed from a philosophical argument stemming from Greek mythology in which new planks replace old ones to maintain Theseus’s Ship for years. “Here, building upon a suggestion of Crick that persistent molecular interactions sustain memory, we tested the hypothesis that the continual coupling between an autonomously active kinase and a postsynaptic scaffolding protein sustains late- LTP and long-term memory,” the team stated. “Thus, as Theseus’ Ship was sustained for generations by continually replacing worn planks with new timbers, long-term memory can be maintained by continual exchange of potentiating molecules at activated synapses, a concept we call persistent synaptic tagging.”

“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,” said Sacktor. “Francis Crick intuited this Theseus’s Ship mechanism, even predicting the role for 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.”

Fenton, who is also on the faculty at the NYU Langone Medical Center’s Neuroscience Institute, further observed, “The persistent synaptic tagging mechanism for the first time explains these results that are clinically relevant to neurological and psychiatric disorders of memory.”