By tweaking genes and administering drugs, scientists have devised a way to selectively erase memories in mice. In the distant future, such work might lead to treatments for soldiers plagued by recurring flashbacks of wartime trauma, the researchers say. But in the meantime, the findings offer insight into the molecular mechanisms of memory storage in the brain.
Several studies in recent years have raised the possibility that even relatively long-lasting memories can be weakened or eliminated with drugs (Science, 2 April 2004, p. 34). Some researchers hypothesize that memories become vulnerable whenever they are recalled and have identified drugs that erode memories when given during recall (ScienceNOW, 25 October 2004). Others have demonstrated memory-erasing effects by blocking an enzyme called PKM-ζ that appears to be necessary for sustaining memories (Science, 17 August 2007, p. 883). The new study adds a third approach to the mix.
Neuroscientist Joe Tsien of the Medical College of Georgia in Augusta and his colleagues used genetic engineering and a drug to manipulate levels of an enzyme called αCaMKII in mice. They created a strain of mice with an extra copy of the gene for αCaMKII, one of a family of enzymes with important roles in neural signaling. Left alone, these engineered mice produced an overabundance of αCaMKII, but the researchers could eliminate the excess with a specially designed inhibitor drug that could be injected or delivered in the mice's drinking water.
With the mice sipping drug-laced water to maintain normal levels of αCaMKII, the researchers trained them to avoid an enclosure where they'd received a mild shock and taught them that a certain tone indicated a forthcoming zap. A month later, the rodents still remembered: They froze up in fear when researchers played the tone or placed them in the enclosure.
But when the researchers withheld the inhibitor drug, allowing excess αCaMKII to flood the brain, memories faded. Mice suddenly forgot to freeze when they heard the tone, for example, even when the researchers restored normal αCaMKII levels and tested them again 2 weeks later. However, only memories recalled during the αCaMKII deluge disappeared: A mouse could forget about the tone and still remember the enclosure, or vice versa, the researchers report in the 23 October issue of Neuron.
The findings represent "another step in a big paradigm shift in how people think about how long-term memories are stored," says Todd Sacktor of State University of New York Downstate Medical Center in New York City, whose lab discovered the memory-erasing effects of PKM-ζ. Neuroscientists have thought for a century that long-lasting memories are encoded by minute changes in brain anatomy, such as alterations to the synaptic connections between neurons, Sacktor says. In that view, he says, it shouldn't be possible to erase memories by meddling with signaling molecules like αCaMKII--especially not within a few minutes, as Tsien's team found.
As for whether these findings could lead to better treatments for post-traumatic stress disorder or other psychiatric conditions, "it's possible," Sacktor says. "The problem is how you would enhance αCaMKII in people since you can't do this genetic trick."