Published online 21 October 2009 | Nature | doi:10.1038/news.2009.1036

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Blocking an enzyme combats some negative effects of sleep deprivation in mice.

Your memory can suffer without some serious shut-eye. PurestockX

A sleepless night can leave your memory in tatters, but research in mice raises the possibility that a drug could counteract the problem.

Although anyone who has ever been deprived of sleep knows all too well how tiredness can affect the brain, the molecular mechanism behind it has eluded researchers. "One of the main problems is that sleep deprivation does a lot of things to the brain, and it's easy to get caught in a mish-mash of different effects," says Christopher Vecsey of Brandeis University in Massachusetts.

Vecsey was part of a team, led by Ted Abel at the University of Pennsylvania in Philadelphia, that examined the effects of sleep deprivation on a region of the brain called the hippocampus. This is well known to have an important role in learning and memory.

The researchers monitored the levels of several molecules in the hippocampi of mice that had been deprived of sleep for five hours. Sleepy mice showed increased levels and activity of an enzyme called PDE4, which acts on a particular suite of molecules that help to consolidate long-term memories.

To confirm that PDE4 was actively impairing memory, the team treated sleep-deprived mice with rolipram, a drug that stops PDE4 from working, and then assessed how well they remembered a fear stimulus. "When we treated [mice] with the drug we found that the memory deficits that they normally would have had with sleep deprivation were prevented," Vecsey says. The results are published in Nature1.

Rolipram and other drugs that inhibit PDE4 are already being researched for their role in disorders such as rheumatoid arthritis and multiple sclerosis. "The problem is that they do have side effects," Vecsey says.

The team's results pointed towards only one particular form of the PDE4 enzyme being affected by sleep deprivation. "If we can design drugs that target this form specifically, successful treatments for some of the cognitive effects of sleep deprivation could be possible," Vecsey says. Such drugs could then be used to boost memory in people with sleep disturbances. But, he says, "it's important to keep in mind also that the type of effects we were examining here are just one aspect of what sleep deprivation can cause in the brain."

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"People knew that sleep deprivation affects learning and memory, but left it there because they didn't really know how it works," says Peter Giese, who studies the biology of memory at the Institute of Psychiatry at King's College London. "This paper is the next milestone because it provides a mechanism."

"It's interesting that not every pathway is affected by sleep deprivation, which was not really known," he adds. "It could have been that all pathways are affected, which would have been a much more complicated result."