| 研究実績の概要 |
In research period, we performed quantitative phosphoproteomic studies of whole mouse brains from two models of sleep/wake perturbation. A combined proteome and phosphoproteome data for 9,410 mouse proteins and 62,384 phosphopeptides were examined. Comparison of two models identifies 80 mostly synaptic Sleep-Need-Index-PhosphoProteins (SNIPPs), whose phosphorylation states closely parallel changes of sleep need. Mutant SLEEPY/SIK3 kinase preferentially associates with and phosphorylates SNIPPs. Inhibition of SIK3 activity reduces phosphorylation state of SNIPPs and slow wave activity (SWA) during non-rapid-eye-movement sleep (NREMS), the best known measurable index of sleep need, in both Sleepy and sleep-deprived wild-type mice. Our results suggest that SNIPPs accumulate/dissipate phosphorylation as the molecular substrate of sleep need. Thus, phosphorylation/dephosphorylation cycle of SNIPPs may represent a major regulatory mechanism that underlies both synaptic homeostasis and sleep-wake homeostasis. These results have been accepted by Nature (In press).
The intracerebroventricular (i.c.v.) injection-based and AAV overexpression-based EEG/EMG sleep recording system have been established, we will investigate the function of Sleepy substrates, such as NOS1 through pharmacological and AAV overexpression approaches.
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