How Do Our Memories Last a Lifetime? New Study Offers a Biological Explanation

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?

A new study in the journal Science Advances, conducted by a team of international researchers, has uncovered a biological explanation for long-term memories. It centers on the discovery of 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," 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 perpetual memory storage."

"A firmer understanding of how we keep our memories will help guide efforts to illuminate and address memory-related afflictions in the future," adds Todd Sacktor, a professor at SUNY Downstate Health Sciences University and one of the study's principal investigators.

Discovery of a "glue" molecule's purpose affirms a concept introduced Nobel Laureate Francis Crick to explain the brain's role in memory storage.

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, thereby 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, or kidney and brain expressed protein, 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-in this case, protein kinase Mzeta (PKMzeta). This enzyme is the most crucial molecule for strengthening normal mammalian synapses that is 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 tag," or glue, that sticks to strong synapses and to PKMzeta 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 experiments in the Science Advances paper show 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 mysterious because it should have done the opposite by acting at random locations, but the persistent synaptic tagging by KIBRA explains why the additional PKMzeta was memory enhancing, by only acting at the KIBRA tagged sites.

Memories are stored by the interaction of two proteins: a structural protein, KIBRA (green), that acts as a persistent synaptic tag, and a synapse-strengthening enzyme, protein kinase Mzeta (red). Drugs that disrupt the memory-perpetuating interaction (other colors) erase pre-established long-term and remote memories. Credit: Changchi Hsieh, Ph.D.

"The persistent synaptic tagging mechanism for the first time explains these results that are clinically relevant to neurological and psychiatric disorders of memory," observes 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 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.

"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," says 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."

The study also included researchers from Canada's McGill University, Germany's University Hospital of Münster, and University of Texas Medical School at Houston.

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 the Garry and Sarah S. Sklar Fund.

About New York University
Founded in 1831, NYU is one of the world's foremost research universities (with more than $1 billion per year in research expenditures, it is ranked seventh among private research universities) and is a member of the selective Association of American Universities. NYU has degree-granting university campuses in New York, Abu Dhabi, and Shanghai; has 13 other global academic sites, including London, Paris, Florence, Tel Aviv, Buenos Aires, and Accra, and US sites in Washington, DC, Los Angeles, CA, and Tulsa, OK; and both sends more students to study abroad and educates more international students than any other U.S. college or university. Through its numerous schools and colleges, NYU is a leader in conducting research and providing education in the arts and sciences, law, medicine, business, dentistry, engineering, education, nursing, the cinematic and performing arts, music and studio arts, public service, social work, public health, and professional studies, among other areas.

About SUNY Downstate Health Sciences University
Downstate Health Sciences University in Brooklyn is one of four academic health centers (AMCs) in the 64-campus State University of New York (SUNY) system and the only SUNY AMC in New York City dedicated to health education, research, and patient care for the borough's 2.7 million residents. Its flagship hospital, University Hospital at Downstate (UHD), is a teaching hospital that benefits from the expertise of Downstate's exceptional medical school and world-class research facilities. Beyond its clinical excellence, Downstate houses a range of esteemed educational institutions, including the College of Medicine, College of Nursing, School of Health Professions, School of Graduate Studies, and School of Public Health. Downstate fosters innovation through its multifaceted biotechnology initiatives, including the Biotechnology Incubator and BioBAT, which support both early-stage and more mature biotech companies. Downstate's research enterprise drives innovation and discovery across a wide array of disciplines. Our investigators are making discoveries that are changing the world and pushing the boundaries of what is possible in biomedicine and healthcare.

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James Devitt

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