Disrupted sleep-wake regulation in type 1 equilibrative nucleoside transporter knockout mice

Area of Science:

• Neuroscience
• Sleep Research
• Molecular Biology

Background:

• Extracellular adenosine ([AD]ex) levels in the basal forebrain (BF) rise during wakefulness and correlate with subsequent non-rapid eye movement sleep (NREMS) delta activity (NRδ), marking sleep homeostasis.
• Waking theta (Wθ) activity also serves as a sleep homeostasis marker, but its hour-by-hour relationship with NRδ is not fully understood.
• The type 1 equilibrative nucleoside transporter (ENT1) is a key regulator of [AD]ex.

Purpose of the Study:

• To investigate the relationship between Wθ and NRδ as EEG markers of sleep homeostasis.
• To examine this relationship in ENT1 gene knockout (ENT1KO) mice during spontaneous sleep-wakefulness, sleep deprivation (SD), and recovery sleep.
• To elucidate the role of ENT1 in regulating wakefulness-associated [AD]ex.

Main Methods:

• Comparison of EEG markers (Wθ and NRδ) between ENT1KO and wild-type (WT) littermate mice.
• Assessment of sleep-wakefulness patterns and their correlation with EEG activity.
• Investigation of the effects of basal forebrain adenosine perfusion and sleep deprivation on EEG markers and [AD]ex levels in ENT1KO mice.

Main Results:

• ENT1KO mice exhibited reduced NREMS during the light period and a weaker correlation between Wθ and subsequent NRδ compared to WT mice.
• Adenosine perfusion in the BF of ENT1KO mice strengthened the Wθ-NRδ relationship and normalized NREMS, suggesting reduced basal [AD]ex.
• Sleep deprivation increased BF [AD]ex and the linear correlation between EEG markers in both WT and ENT1KO mice, indicating ENT1-independent mechanisms contribute to adenosine regulation during prolonged waking.

Conclusions:

• ENT1 plays a role in maintaining normal NREMS and the temporal coupling of EEG markers of sleep homeostasis during spontaneous sleep-wakefulness.
• Reduced [AD]ex in ENT1KO mice contributes to altered sleep homeostasis markers.
• Wakefulness-associated [AD]ex regulation differs between spontaneous waking and prolonged sleep deprivation, with non-ENT1 sources becoming significant during extended wakefulness.