Brain Scientists Finally Discover the Glue that Makes Memories Stick for a Lifetime

6 min read

A long-running research endeavor reveals key chemical players that cement memories in place—and still more have yet to be discovered

By Simon Makin Synapse Sebastian Kaulitzki/Science Photo Library/Getty Images The persistence of memory is crucial to our sense of identity, and without it, there would be no learning, for us or any other animal. It’s little wonder, then, that some researchers have called how the brain stores memories the most fundamental question in neuroscience.

A milestone in the effort to answer this question came in the early 1970s, with the discovery of a phenomenon called long-term potentiation, or LTP. Scientists found that electrically stimulating a synapse that connects two neurons causes a long-lasting increase in how well that connection transmits signals. Scientists say simply that the “synaptic strength” has increased. This is widely believed to be the process underlying memory. Networks of neural connections of varying strengths are thought to be what memories are made of.

In the search for molecules that enable LTP, two main contenders emerged. One, called PKMzeta (protein kinase Mzeta), made a big splash when a 2006 study showed that blocking it erased memories for places in rats. If obstructing a molecule erases memories, researchers reasoned, that event must be essential to the process the brain uses to maintain memories. A flurry of research into the so-called memory molecule followed, and numerous experiments appeared to show that it was necessary and sufficient for maintaining numerous types of memory. On supporting science journalism

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The theory had a couple of holes, though. First, PKMzeta is short-lived. “Those proteins only last in synapses for a couple of hours, and in neurons, probably a couple of days,” says Todd Sacktor, a neurologist at SUNY Downstate Health Sciences University, who was co-senior author of the 2006 study. “Yet our memories can last 90 years, so how do you explain this difference?” Second, PKMzeta is created in cells as needed, but then it has to find the right synapses. Each neuron has around 10,000 synapses, only a few percent of which are strengthened, says neuroscientist Andre Fenton, the other co-senior author of the 2006 study, who is now at New York University. The strengthening of some synapses and not others is how this mechanism stores information, but how PKMzeta molecules accomplish this was unknown.

A new study published in Science Advances by Sacktor, Fenton and their colleagues plugs these holes . The research suggests that PKMzeta works alongside another molecule, called KIBRA (kidney and brain expressed adaptor protein), which attaches to synapses activated during learning, effectively “tagging” them. KIBRA couples with PKMzeta, which then keeps the tagged synapses strengthened.

Experiments show that blocking the interaction between these two molecules abolishes LTP in neurons and disrupts spatial memories in mice. Both molecules are short-lived, but their interaction persists. “It’s not PKMzeta that’s required for maintaining a memory, it’s the continual interaction between PKMzeta and this targeting molecule, called KIBRA,” Sacktor says. “If you block KIBRA from PKMzeta, you’ll erase a memory that’s a month old.” The specific molecules will have been replaced many times during that month, he adds. But, once established, the interaction maintains memories over the long term as individual molecules are continually replenished.

The findings boost a theory that has seen some pushback. In 2013 two studies showed that mice genetically engineered to lack PKMzeta could form long-term memories. Furthermore, the molecule researchers had used to block PKMzeta in the earlier studies — known as ZIP (zeta-inhibitory peptide)—also abolished memories in these mice, showing that it must be interacting with some other molecule. Three years later Sacktor and Fenton proposed an explanation. The researchers published a study suggesting that another, related protein, PKCiota/lambda, stepped in to take over PKMzeta’s job in animals engineered to lack PKMzeta from birth. PKCiota/lambda exists in normal animals’ synapses in small and fleeting quantities, but the researchers found that it was greatly elevated in mice lacking PKMzeta. They also showed that ZIP blocks PKCiota/lambda, which explains why it erased memories in the engineered mice.

This became a serious criticism of PKMzeta studies: ZIP’s effects were not as specific as originally thought. Not only does it block molecules other than PKMzeta, but one study also found that it even suppresses brain activity .

The new study addresses this issue. The researchers used two different molecules to block PKMzeta and KIBRA from interacting. They first showed that both of these blockers only prevent PKMzeta from attaching to KIBRA. Neither stop PKCiota/lambda from doing so. Experiments showed that both blockers reversed LTP and disrupted memories in normal mice but had no effect on memory storage in mice engineered to lack PKMzeta. “Evidence is more trustworthy when you have converging results showing the same thing with different methods,” says Janine Kwapis, a neuroscientist at Pennsylvania State University, who was not involved in the study. “It’s really convincing.”

The results show that blocking PKMzeta—but not PKCiota/lambda—in normal, nonengineered animals erases memories, so under ordinary circumstances, iota/lambda cannot be crucial to long-term memory storage because its presence in the brain does not prevent memories being erased. “We nailed it,” Sacktor says. “There’s no getting away from [the conclusion that] PKMzeta is critical.” Fenton and Sacktor think PKCiota/lambda is an evolutionary relic that was involved in memory eons ago. Once PKMzeta evolved, it replaced iota/lambda, and it does a better job. But when scientists knock out the PKMzeta gene in laboratory animals, the animals compensate by falling back on iota/lambda.

The study also makes sense of a previously puzzling finding. In 2011 Sacktor and colleagues showed that boosting PKMzeta in rats enhanced old memories . “You could enhance a memory that had almost but not quite gone,” Sacktor says. “That had never been seen before.” This was unexpected because indiscriminately strengthening synapses should weaken memories, not strengthen them. “That was a weird finding,” says […]

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