Enzyme Can Alter Long-Term Memories

A neuron in a rat brain's cortex over-expressing PKMzeta (blue).Dr. Todd Sacktor, SUNY Downstate Medical Center.

Even long after memories have formed, they can be enhanced or erased by altering the activity of a single brain enzyme, a new study reveals. The finding may give insight into potential strategies for treating a variety of memory disorders.

Researchers have made significant advances in enhancing or disrupting memories, but these generally involve manipulations during short windows of time just after learning or upon retrieval of a memory. Memories seem to be temporarily fragile and changeable during these time-limited windows. But until recently, no method has been shown to affect memories formed outside these windows, such as ones from the distant past.

Scientists previously showed that a brain enzyme called PKMzeta is critical for the integrity of previously established memories. In animal models, the enzyme seems to play a central role in maintaining the integrity of long-term memories induced using a variety of well-established behavioral learning methods.

In their latest study, the team — led by Dr. Todd Sacktor of the SUNY Downstate Medical Center in New York City and Dr. Yadin Dudai of the Weizmann Institute of Science in Rehovot, Israel — further explored the effects of manipulating PKMzeta levels in the brain. Their work was partly supported by NIH’s National Institute of Mental Health (NIMH).

The researchers paired genetic engineering with a model called conditioned taste aversion that they had used in their previous work. Rats were taught to associate a nauseating sensation with saccharin and so to shun the sweet taste. Seven days after the animals were trained, the researchers used a virus to overexpress either PKMzeta or a mutant inactive form of the enzyme. The scientists infused these viruses into the insular cortex, a part of the brain that their previous work had shown was critical for the taste aversion memory. The results appeared in Science on March 4, 2011.

Overexpression of PKMzeta, the researchers found, significantly enhanced taste aversion memories. This was true of memories that had already been formed as well as memories formed after the transgene was infused. When the researchers trained the rats to shun 2 different tastes at different times, PKMzeta overexpression enhanced the long-term memory of both. Expression of the inactive form of PKMzeta, in contrast, erased the memories — much as a chemical blocker had in their previous study.

"Our study is the first to demonstrate that, in the context of a functioning brain in a behaving animal, a single molecule, PKMzeta, is both necessary and sufficient for maintaining long-term memory," says Sacktor.

This approach affects multiple memories stored in the targeted brain area. Further work will be needed to understand how to home in on specific memories to treat conditions such as post-traumatic stress disorder. The discovery could also point the way toward new types of memory enhancers for treating amnesia or cognitive decline.