Memory Molecule Theory Debunked By New Study
January 2, 2013

Study Rocks Research Community By Debunking Memory-Molecule Theory

Jedidiah Becker for — Your Universe Online

A recent study by neuroscientists at Johns Hopkins University has torn the bottom out of a widely accepted theory about how the brain creates memories. The old paradigm held that the ability to form long-term memories depended largely on the activity of a single enzyme in the brain, a notion that now appears to be entirely incorrect.

In a report of their research published in the January 2 issue of the journal Nature, the researchers described how an experiment with mice inadvertently demonstrated that the enzyme in question — known as PKM-zeta — cannot be as critical as once thought, since mice that lacked the enzyme were still able to create long-term memories.

"The prevailing theory is that when you learn something, you strengthen connections between your brain cells called synapses," explained Richard Huganir, Ph.D., a professor and director of the Johns Hopkins University School of Medicine's Department of Neuroscience. "The question is, how exactly does this strengthening happen?"

In 2007, researchers at SUNY Downstate in Brooklyn believed that they had found the answer to this question. Led by Professor of Neurology Todd Sacktor, the SUNY team made a stir in the neuroscience community when they discovered that they could erase the existing long-term memory of mice by giving them injections of a molecule known as ZIP in the hippocampus, a region of the brain associated with memory formation. Since ZIP is known to block the activity of PKM-zeta, a consensus quickly arose in the research community that the enzyme was responsible for the creation of long-term memories.

While the remarkable results of the experiment unleashed a barrage of references to the film Eternal Sunshine of the Spotless in the media and blogosphere, neuroscientists viewed it as a rare opportunity to explore just how the PKM-zeta enzyme functioned in memory formation.

"Since 2006, many papers have been published on PKM-zeta and ZIP, but no one knew what PKM-zeta was acting on," explained Lenora Volk, a postdoctoral fellow at Johns Hopkins and a member of Huganir's team.

"We thought that learning the enzyme's target could tell us a lot about how memories are stored and maintained."

For their recent study, Huganir´s team wanted to explore how PKM-zeta works by comparing the synapses of normal mice with those of mice that lacked the gene for the enzyme. In order to do that, they first used a modern lab technique known as “genetic knockout” to create a strain of mice that did not produce the PKM-zeta enzyme.

What the team expected was a genetically modified breed of mice that would be incapable of strengthening their synapses and would therefore be unable to form long-term memories. But as Volk said in a statement: “[W]hat we got was not at all what we expected.”

According to the report on their study, the team was able to find no difference between the brain function of normal mice and the mice that lacked the PKM-zeta gene. Equally surprising, in both the normal and ℠knockout´ strains of mice, the memory-erasing ZIP molecule was still able to block the formation of long-term memories — providing further evidence that the memory enzyme is not involved in memory formation in the way scientists previously believed.

Not entirely convinced by the unexpected results, the team hypothesized that perhaps the ℠knockout´ mice were able to develop an alternative pathway for building long-term memories in the absence of the PKM-zeta enzyme.

To test this alternate-pathway theory for memory-building, they created yet another strain of mice that possessed a normally functioning PKM-zeta gene with one small modification: The researchers could shut down the production of the PKM-zeta enzyme by injecting the mice with a specific drug. By doing this, they were able to remove the enzyme from the mice just before injecting them with the ZIP molecule, thus leaving their brains no time to develop an alternate pathway for strengthening synapses.

But to their surprise, the third strain of mice reacted to the tests exactly like the other two types. The new mice, just like the normal and PKM-zeta-less ones, demonstrated normal long-term memory formation until they were injected with the amnesia-inducing ZIP molecule.

While neuroscientists around the world will now be scrambling to interpret all the implications of this minor scientific revolution, one thing is clear: The PKM-zeta enzyme is not the central player in long-term memory formation as most researchers have believed for the past six years.

"We don't know what this ZIP peptide is really acting on," explained Volk. "Finding out what its target is will be quite important, because then we can begin to understand at the molecular level how synapses strengthen and how memories form in response to stimuli."