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

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.

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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 Ryan Parsons, a neuroscientist at Stony Brook University, who was not involved in the work. But it gave Sacktor and Fenton a useful hint. “It’s a clue that something must be specifying where PKMzeta acts,” Fenton says, “which we then looked for.”

Two lines of evidence gave them reason to suspect KIBRA. In humans, different variants of the KIBRA gene have been linked to better or worse memory, while animal studies have shown that interfering with KIBRA disrupts memory. Using techniques for visualizing close associations between KIBRA and PKMzeta, the researchers found that these pairings increased in synapses that they stimulated. This is presumably why boosting PKMzeta can enhance memories. KIBRA ensures it only strengthens certain synapses. “There was an assumption that there must be some molecule that’s binding [PKMzeta to synapses],” Parsons says. “But they were never able to identify one until now.” It is tempting to view this as a culmination of two decades of effort, but the scientists insist it is just the beginning. Next on their agenda is figuring out what keeps the interaction going. They are also investigating how strengthened synapses are distributed on neurons. “Are they all together, near the cell body, [or] distributed randomly?” Fenton asks. Knowing the answer might inform efforts to treat conditions that impair memory, such as Alzheimer’s disease, he says.

As a neurologist, Sacktor says he already sees implications of the work for therapies. “I’m seeing more and more the possibilities of directly putting proteins in neurons through gene therapy,” he says, adding that the idea of being able to rejuvenate memories is no longer far-fetched. Drugs that could erase memories therapeutically to treat post-traumatic stress disorder (PTSD), for example, are trickier to imagine. “If you wanted to use this sort of mechanism to target unwanted memories—which creates ethical issues anyways—you’d have to find a way to make it specific to certain memories,” Parsons says. “And I don’t know what that would look like.”

Other questions persist. For starters, there are competing theories to consider. The other candidate for the mantle of “memory molecule” is an enzyme called CaMKII. Sacktor and Fenton think CaMKII is involved in processes that initiate learning, rather than the mechanism of long-term storage of memories per se, but not everyone agrees. “If I had to pick another molecule, CaMKII is probably the best contender,” Kwapis says.

What seems clear is that there is no single “memory molecule.” Regardless of any competing candidate, PKMzeta needs a second molecule to maintain long-term memories, and there is another that can substitute in a pinch. There are also some types of memory, such as the association of a location with fear, that do not depend on PKMzeta. Nobody knows what molecules are involved in those cases, and PKMzeta is clearly not the whole story. “The intriguing possibility is that there’s a molecular logic of how you make a long-lasting memory that can be carried out in multiple ways with different components,” Fenton says. “Whether it’s PKMzeta or CaMKII or whatever else doesn’t matter so much, but identifying that logic allows us to go look for the right kinds of elements and interactions.”