It’s funny, although we spend about a third of our lives doing it, we don’t know exactly why we need to sleep. There are a number of different theories—that we sleep to conserve energy, for brain plasticity, or for evolutionary reasons. Whatever the true purpose of sleep may be, researchers are delving deeper into the molecular reasons behind why we have the desire to go to sleep, and, in the process, could shed light on the purpose of sleep as well.

Qinghua Liu and colleagues studied the molecular need for sleep by developing a special type of mutant mouse. The mutant genotype was called Sleepy, like Snow White’s dwarf, and had a single mutation in the Sik3 gene. These mice had a much higher need to sleep although they slept a lot. Their brains showed a ton of phosphorylation, similar to those in sleep-deprived mice. The mutant protein in Sleepy mice phosphorylates at a greater rate.

“To study the molecular basis of sleep need, we devised a novel strategy of comparing phosphorylation in the brains of the sleep-deprived normal mice and Sleepy mutant mice. In Sleepy mice, a single nucleotide mutation of the salt-induced kinase 3 (Sik3) gene, a member of the AMP-activated protein kinase family, results in constitutively high sleep need and chronic hypersomnia. Whereas sleep deprivation increases wake time, Sleepy mutation decreases wake time; yet both increase sleep need. Thus, these mice are two opposite models of increased sleep need. We hypothesize that cross-comparison of these two models will allow us to zero in on the specific phosphorylation changes associated with sleep need by filtering out non-specific effects of prolonged sleep, wake, and stress, which can never be achieved by either model alone,” said Liu to ZME Science.

Image credits: Public Domain Photos.

Phosphorylation entails the attachment of a phosphoryl group to a molecule. It is an important regulatory mechanism in living organisms that is usually reversible. Phosphorylation and dephosphorylation function as “on” and “off” switches for a variety of different enzymes and receptors.

By comparing Sleepy and sleep-deprived mice, the researchers were able to identify 80 synaptic proteins that were phosphorylated due to a lack of sleep and named them Sleep-Need-Index-Phosphoproteins (SNIPPs). Comparing these two mouse types filtered out confounding effects and they could see what really changed on a molecular basis. High phosphorylation levels in the brain increased the need for sleep and sleeping lowered phosphorylation levels.

“A holy grail of sleep research is to identify the actual molecular factor or factors involved in sleep. We found that the phosphorylation of SNIPPs increased along with sleep need and dissipated, or dephosphorylated, throughout the brain during sleep.  Previous studies suggested a close link between sleep need and synaptic plasticity (the strengthening and weakening of synaptic connections between neurons that is linked to thinking and learning). Intriguingly, the majority of SNIPPs are synaptic proteins, including many regulators of synaptic plasticity. Thus, we propose that SNIPPs constitute the molecular interface between synaptic plasticity and regulation of sleep need, or in lay terms, between thinking and sleepiness.

The phosphorylation/dephosphorylation cycle of SNIPPs may be an important way for the brain to reset itself every night, restoring both synaptic and sleep-wake balance to maximize clear thinking,” explained Liu to ZME Science.

Synapse phosphorylation seems to be a sign that you need sleep. These results are interesting because they match up with the synaptic homeostasis hypothesis, which proposes that sleep allows synapses to recover from their daily activity and keep everything going stably. When you’re awake memories are encoded and synapses fire, while during sleep memories are consolidated and synapses are brought back to homeostasis by scaling back excitatory synapses.

These findings add to our knowledge about sleep and provide concrete targets for drugs that can treat sleep disorders.

Journal reference: Liu et al. 2018. Quantitative phosphoproteomic analysis of the molecular substrates of sleep need. Nature.