5’-ectonucleotidase knockout mice lack non-REM sleep responses to sleep deprivation

Adenosine and extracellular adenosine triphosphate (ATP) have multiple physiological central nervous system (CNS) actions including regulation of cerebral blood flow, inflammation, and sleep. However, their exact sleep regulatory mechanisms remain unknown. Extracellular ATP and adenosine diphosphate (ADP) are converted to adenosine monophosphate (AMP) by the enzyme ectonucleoside triphosphate diphosphohydrolase 1, also known as CD39, and extracellular AMP is in turn converted to adenosine by the 5’-ectonuleotidase enzyme CD73. We investigated the role of CD73 in sleep regulation. Duration of spontaneous non-rapid eye movement sleep (NREMS) was greater in CD73 knockout (KO) mice compared to C57BL/6 controls whether determined in our laboratory or by others. After sleep deprivation (SD), NREMS was enhanced in controls but not CD73 KO mice. Interleukin-1 beta (IL1β) enhanced NREMS in both strains indicating that the CD73 KO mice were capable of sleep responses. Electroencephalographic (EEG) power spectra during NREMS in the 1.0–2.5 Hz frequency range was significantly enhanced after SD in both CD73 KO and WT mice; the increases were significantly greater in the WT mice vs. CD73 KO mice. Rapid eye movement sleep did not differ between strains in any of the experimental conditions. With the exception of CD73 mRNA, the effects of SD on various adenosine-related mRNAs were small and similar in both strains. These data suggest that sleep is regulated, in part, by extracellular adenosine derived from the actions of CD73.