Controlling long-term memory

Harvard University biologists have identified a molecular pathway active in neurons that interacts with RNA to regulate the formation of long-term memory in fruit flies. The same pathway is also found at mammalian synapses, and could eventually present a target for new therapeutics to treat human memory loss.

The findings were presented Jan. 12 on the Web site of the journal Cell.

Even for a fruit fly, learning and memory are important adaptive tools that facilitate survival in the environment. A fly can learn to avoid what may do it harm, such as a flyswatter, or, in the laboratory, an electric shock that happens when it smells a certain odor.

“It has been known for some time that learning and long-term memory require synthesis of new proteins, but exactly how protein synthesis activity relates to memory creation and storage has not been clear,” says Sam Kunes, professor of molecular and cellular biology in Harvard’s Faculty of Arts and Sciences. “We have been able to monitor, for the first time, the synthesis of protein at the synapses between neurons as an animal learns, and we found a biochemical pathway that determines if and where this protein synthesis happens. This pathway, called RISC, interacts with RNA at synapses to facilitate the protein synthesis associated with forming a stable memory. In fruit flies, at least, this process makes the difference between remembering something for an hour and remembering it for a day or more.”

Together with lead author Shovon Ashraf, a postdoctoral researcher in Harvard’s Department of Molecular and Cellular Biology, and Anna McLoon ’04 and Sarah Sclarsic ’06, Kunes found that messenger RNA (mRNA) – a genetic photocopy that conveys information from DNA to a cell’s translation machinery – is transported to synapses as a memory begins to form. This mRNA transport, and the protein synthesis that follows, are facilitated by components of the RISC pathway, which use very short RNA molecules called microRNAs to guide their activity. One of these RISC proteins, called Armitage, appears to be a critical regulatory molecule in long-lasting memory formation, and has to be destroyed at particular synapses in order for protein synthesis to occur there.

By manipulating the RISC pathway, Kunes and colleagues were able to alter flies’ memory, changing their response to stimuli in subsequent behavioral tests. Using a classical learning test that simultaneously exposes the insects to an odor and an electric shock, the researchers found that long-term memory could be greatly increased by adjusting the activity of the RISC pathway in the fruit flies.

“In essence, these flies had twice the memory of their normal counterparts,” Kunes says. “When RISC was knocked out, so was long-term memory, and flies would remember to alter their behavior in the presence of the shock-linked odor for perhaps an hour; that is, they only had short-term memory. When the pathway was normally active, the flies remained averse to the odor for a day or more.”

Kunes says the various proteins that comprise the RISC pathway are also found at synapses in mice and humans, suggesting the pathway has been conserved by evolution and that it could be a target for new medications to boost human memory.

This research was funded by Harvard’s Faculty of Arts and Sciences.