It's easy to take sleep for granted; after all, for most of us it's something we do every night with relative ease. However, our ability to fall, and stay, asleep is tightly regulated. In mammals, it is controlled by at least three different centres in our brain and so many researchers have turned to the simpler fruit fly instead: ‘In flies there is at least a hint that perhaps it's much simpler and that the three centres are just located in a small subset of neurons, called the large ventrolateral neurons’, explains Charlotte Helfrich-Förster, a researcher at the University of Würzburg, Germany. Helfrich-Förster goes on to explain that these small insects have already highlighted the role the neurotransmitter GABA plays during sleep: ‘If you down regulate GABA in the fly, you find that they have difficulties in falling asleep and finally, after they have fallen asleep, they also wake up earlier.’ However, when researchers blocked the GABAA receptor subtype, they found that flies had no problem maintaining sleep, just difficulties in drifting off. So, how was GABA helping flies stay in their state of slumber if not through GABAA? Helfrich-Förster decided to investigate (p. 3837).
Helfrich-Förster and her team knew of a second type of GABA receptor, called GABAB receptors, which act via a slower mechanism than GABAA receptors, and wondered whether they might be responsible for maintaining GABA-induced sleep. However, first the team needed to see whether GABAB receptors were also found in the same ventrolateral (l-LNV) region as the GABAA receptors. Sure enough, using an antibody targeting GABAB receptors, the team were able to show that the receptors were present in the region of the fly brain that controls sleep.
Next, the team needed to deplete these l-LNV neurons of GABAB receptors. Luckily, Dick Nässel, from Stockholm University, Sweden, already had fly lines where they could reduce expression of the GABAB gene specifically in the l-LNV region. To test what affect this reduction of GABAB was having on the flies, the team then needed to monitor their sleeping patterns: ‘Of course, it is not as easy as in mammals because we cannot record an EEG [electroencephalogram measuring electrical activity]’, says Helfrich-Förster. ‘So, instead, we monitored the activity of the flies using an infrared light beam; when they interrupt the beam it was recorded as being active and when the flies are inactive for more than 10 min it was recorded as sleeping.’ During the first 12 daylight hours all the flies followed the same routine, including a mid-day snooze, and when it came to lights-out all the flies dozed off just as quickly as each other. However, during the second half of the night, half an hour before most flies were waking up, flies with reduced GABAB levels became more active.
To double check that the reduction of GABAB wasn't due to a change in the circadian clock, the team kept the flies in constant darkness for 24 h a day for 10 days and found there was no difference between flies with or without GABAB in the l-LNV region. Helfrich-Förster's research has finally answered the question of how GABA keeps flies asleep and it's quite possible the same is true for us. So, if you're having difficulties staying asleep perhaps it's time to blame your GABAB receptors.
