Prions, proteins better known for the “negative” role they play in spreading mad cow disease, may also have a positive and important role in helping memories persist.
This tentative suggestion was the conclusion of a study by Dr Kausik Si of Stowers Institute for Medical Research, Kansas City, Missouri, Nobel laureate Dr Eric Kandel of the College of Physicians and Surgeons of Columbia University, New York, and colleagues, published on 5 February in the journal Cell.
Si told the media that:
“The persistence of memory is a fundamental problem. Experiences are temporal; they happen once, but somehow must lead to changes [in the brain] that are somewhat permanent.”
These changes must come about via molecules, including proteins, said Si, but a significant question remains:
“How can you maintain a stable state with unstable biological molecules?”
In this latest study, Si and colleagues believe they may have found that prions hold the clue.
Prions are able to take on two states, one of which is dominant and self-perpetuating so that once a protein takes on this state it converts other non-prion proteins to the same state: thus once the prion state is switched on, it becomes stable and self-renewing.
For the study, Si and colleagues focused on the sea slug Aplysia, which scientists have been using for decades in experiments involving memory and learning.
When you touch this sea slug’s gills, they withdraw, and when you “train” the animals by giving them a shock at the same time, the withdrawal reaction becomes stronger for up to a month.
Scientists had already discovered that this learned behaviour came about because of a specific set of sensory and motor neurons that respond to serotonin.
But in this study, Si and colleagues took a closer look at the proteins hanging around the synapse at the point where serotonin becomes active: one of these was a protein called CPEB, which when they looked at its structure, resembled prions that scientists had discovered a while ago in yeast, and which had known functions.
In an earlier study, Si had reported that slug protein did not display prion-like properties when inserted into yeast, but in this study, they found that the proteins switch to their prion state and clump together (typical behaviour for prions) in the presence of serotonin, as they did in the Aplysia sensory neurons.
To confirm this idea, the researchers used an antibody to target the clumped prion protein and found it blocked the persistence of neural connections that form the cellular basis for learning and memory.
Si and colleagues said that the findings suggest memory traces may depend on a fairly unique mechanism involving the prion form of CPEB. This adds to a growing body of evidence that prions may have a broader role in biology other than causing diseases.
They concluded that:
“These results are consistent with the idea that ApCPEB can act as a self-sustaining prion-like protein in the nervous system and thereby might allow the activity-dependent change in synaptic efficacy to persist for long periods of time.”
However, Si cautioned that they haven’t yet proved that blocking CPEB’s ability to perpetuate itself actually blocks memory. To do that they would have to show that a slug with a mutant form of the protein would learn but then quickly forget.
The findings offer “at least an idea” of how memory might persist, said Si, who suspects that the prion-like protein’s role apparent role in memory may just turn out to be a more general phenomenon.
Si and colleagues are now looking at CPEB in flies, and he noted that humans also have a similar protein.
“Aplysia CPEB Can Form Prion-like Multimers in Sensory Neurons that Contribute to Long-Term Facilitation.”
Kausik Si, Yun-Beom Choi, Erica White-Grindley, Amitabha Majumdar, Eric R. Kandel.
DOI: 10.1016/j.cell.2010.01.008
Source: Cell Press.
Written by: Catharine Paddock, PhD