Hyperkinetic (Hk) is the second gene identified by the SMPH group to have a profound effect on sleep in flies.

The finding supports growing evidence that potassium channels--found in humans and fruit flies alike--play a critical role in generating sleep.

"Without potassium channels, you don't get slow waves, the oscillations shown by groups of neurons across the brain that are the hallmark of deep sleep," says Chiara Cirelli, SMPH psychiatry professor and senior author on the latest study, which appeared in the May 16, 2007, Journal of Neuroscience .

The researchers are searching for compounds that could regulate the small Hk gene and thereby modulate the amount of potassium that enters cells-control that could help people avoid insomnia or stay alert.

Cirelli and her colleagues believe that the new fly findings have clear and strong implications for human sleep since all mammals have similar potassium-controlling genes.

Furthermore, Cirelli and Giulio Tononi, also an SMPH psychiatry professor, have found many additional similarities between fly sleep and human sleep: like humans, fruit flies generally are quiet and immobile for between six and 12 hours each night and lose most of their ability to respond to stimuli; sleep-deprived humans and their winged counterparts rebound on the following night by sleeping longer and more deeply; and as with humans, flies sleep more in their youth than later in life, when their sleep is fragmented.

In the current study, Daniel Bushey, a post-doctoral fellow in Cirelli's lab, focused on Hk because it binds to Shaker (Sh), a large gene that codes for the membrane pore by which potassium enters cells. Hk regulates the size of the pore, which determines how much potassium exits the cell.

In an earlier study in the journal Nature in April 2005, SMPH scientists discovered that mutations in Sh significantly affected sleep, producing flies that sleep much less than do normal flies. Now they have demonstrated that mutations in Hk also reduce sleep by affecting the Sh current. The researchers unequivocally confirmed the finding by substituting a normal copy of Hk into the mutated flies, which then restored normal sleep.

"This transgenic approach proved that Hk is required to maintain normal sleep in fruit flies," Cirelli says, adding that the team was not able to do the same with Sh due to the size of the gene.

The researchers also found genetic evidence that short sleeping flies containing mutated Hk genes exhibited memory deficits when they were challenged with a new task. Once again, when a normal Hk was inserted, normal memory returned. "We showed a perfect link between short-sleeping flies and impaired memory, but this doesn't necessarily prove a causal relationship," Cirelli says. "However, it's a correlation we're very interested in."

The correlation ties in neatly with a theory Tononi and Cirelli have developed that they call the synaptic homeostasis hypothesis.

"While we are awake, synapses in our brains get stronger as we learn new things, some of which we are not even aware of learning," Cirelli explains. But the brain cannot sustain an unending build-up of synapses, and that's where sleep plays such a crucial role, according to the hypothesis.

We believe that sleep's specific function is to down-regulate some of the synaptic connections that are potentiated during waking hours," Cirelli says. "If this doesn't occur, new synaptic connections cannot be made and, as a result, we cannot learn or remember as well as when we get enough sleep."

Sleep is so critical to learning, remembering and staying healthy that several genes are likely involved, says Cirelli, and the genes probably control several kinds of membrane channels. But in all likelihood, Hk plays a major role.

wisc/