Scientists have found the first step toward discovering the biochemistry that controls the switch from wakefulness to sleep. The first unbiased genetic screen for sleep defects in mice has resulted in two interesting mutants: Sleepy, which sleeps excessively, and Dreamless, which lacks rapid eye movement (REM) sleep.

In their report in Nature, researchers have theorized that there is a substance that accumulates during our waking hours, only to be discharged or recovered while we sleep. "But we still don't understand those processes," said Howard Hughes Medical Institute investigator Joseph Takahashi at the University of Texas Southwestern Medical Center in Dallas.

Takahashi and Masashi Yanagisawa, a professor in the International Institute for Integrative Sleep Medicine at the University of Tsukuba in Japan, had decided to take an unbiased exploratory approach. Instead of beginning with a hypothesis about specific genes that might be involved, the researchers introduced random genetic mutations in more than 8,000 mice and screened them using electroencephalography (EEG) to identify which mice had abnormal sleep as a result of the genetic alteration.

"The barrier in the past has been that it's a very laborious process. To do a genetic screen, you should be prepared to screen thousands of animals before you find something interesting, and most people are just not willing to measure EEGs in thousands of mice," explained Takahashi.

The researchers identified two mutations, which they called Sleepy and Dreamless, and subsequently mapped them to locations in the mouse genome. Sleepy mice, which need approximately one-third more sleep than normal mice, carry a mutation in the Sik3 kinase gene. Since the Sleepy mice had normal arousal responses to environmental and pharmacological stimuli and had no circadian rhythm disturbance, scientists concluded that Sleepy mice had an increased sleep need, but the physiological reasons for that remained unclear. "Sleep need still remains a mystery, but what we hope is that this kinase is maybe the key, the initial key to this big door," said Yanagisawa.

Dreamless mice have a mutation in a sodium channel, increasing the conductivity of a leaky sodium channel that was previously known to regulate neuronal excitability. Since the mice's neuronal populations have too much excitability, they terminate REM sleep for the mice.

The researchers believe that the screen will result in more mutants with sleep defects to investigate. "We really hope that this is opening up some mysteries. This is just the beginning," said Yanagisawa.