What makes memories last?

Finding the molecular alterations that encode a memory in specific neurons as it endures for days, months, or years—even as the cells’ proteins are degraded and renewed—is a focus of research in the lab of Investigator Kausik Si, PhD. Increasingly, their research is pointing toward prion-like proteins as critical regulators of long-term memory.

Prions can be notoriously destructive, spurring proteins to misfold and interfere with cellular function as they spread without control. Certain prion-like proteins, however, can be precisely controlled so that they are generated only in a specific time and place. These prion-like proteins are not involved in disease processes; rather, they are essential for creating and maintaining long-term memories. “This protein is not toxic; it’s important for memory to persist,” says Si who led the study in collaboration with researchers at the University of Kansas Medical Center.

Si’s team had previously found that in fruit flies, the prionforming protein Orb2 is necessary for memories to persist. Fruit flies that produce a mutated version of Orb2 that is unable to form prions learn new behaviors, but their memories are short-lived.

In the new study, Si wanted to find out how this process could be controlled so that memories form at the right time. “We know that all experiences do not form long-term memory—somehow the
nervous system has a way to discriminate. So if prion-formation is the biochemical basis of memory, it must be regulated.” Si says Si and his colleagues knew that Orb2 existed in two forms—Orb2A and Orb2B. Orb2B is widespread throughout the fruit fly’s nervous system, but Orb2A appears only briefly in a few neurons, at extremely low concentrations. Their experiments revealed that when a protein called TOB associates with Orb2A, Orb2A becomes much more stable and longer lived which increases the prevalence of the prion-like state.

The findings raise a host of new questions for Si, who now wants to understand what happens when Orb2 enters its prion-like state, as well as where in the brain the process occurs.

The study was published in the February 11, 2014, issue of PLOS Biology.