Abstract
Increasing evidence suggests that clock genes may be implicated in a spectrum of psychiatric diseases, including sleep and mood related disorders as well as schizophrenia. The bHLH transcription factors SHARP1/DEC2/BHLHE41 and SHARP2/DEC1/BHLHE40 are modulators of the circadian system and SHARP1/DEC2/BHLHE40 has been shown to regulate homeostatic sleep drive in humans. In this study, we characterized Sharp1 and Sharp2 double mutant mice (S1/2-/-) using online EEG recordings in living animals, behavioral assays and global gene expression profiling. EEG recordings revealed attenuated sleep/wake amplitudes and alterations of theta oscillations. Increased sleep in the dark phase is paralleled by reduced voluntary activity and cortical gene expression signatures reveal associations with psychiatric diseases. S1/2-/- mice display alterations in novelty induced activity, anxiety and curiosity. Moreover, mutant mice exhibit impaired working memory and deficits in prepulse inhibition resembling symptoms of psychiatric diseases. Network modeling indicates a connection between neural plasticity and clock genes, particularly for SHARP1 and PER1. Our findings support the hypothesis that abnormal sleep and certain (endo)phenotypes of psychiatric diseases may be caused by common mechanisms involving components of the molecular clock including SHARP1 and SHARP2.
Highlights
The circadian system has been implicated in the control of alertness and clock genes have been associated with sleep and mood disorders, such as familial advance sleep phase syndrome (FASPS), depression, mania or bipolar disease (BD) [1,2,3,4,5,6,7,8], and therapeutic approaches modulating the circadian system (‘chronotherapy’) may be promising to improve treatment of psychiatric diseases [9,10]
Attenuated Sleep-Wake Amplitudes in S1/2-/- mice Given the relatively mild sleep phenotype of Sharp1 single mutants [38] and the functional redundancy of SHARP1 and -2 [35], we focussed on the analysis of Sharp1 and -2 double mutant mice (S1/2-/-)
Sleep-wake behavior was quantified as relative L-D differences, which were significantly reduced in S1/ 2-/- animals for all three vigilance states (p,0.01 for wake, p,0.05 for rapid eye movement sleep (REM) and non-rapid eye movement (NREM) sleep) (Figure 1B)
Summary
The circadian system has been implicated in the control of alertness and clock genes have been associated with sleep and mood disorders, such as familial advance sleep phase syndrome (FASPS), depression, mania or bipolar disease (BD) [1,2,3,4,5,6,7,8], and therapeutic approaches modulating the circadian system (‘chronotherapy’) may be promising to improve treatment of psychiatric diseases [9,10]. Prolonged wakefulness results in compensatory or rebound sleep, and disruption of normal sleep-wake cycles may contribute to psychiatric symptoms and inflammatory as well neurodegenerative processes [16,17]; sleep deprivation has been shown to have short term beneficial effects in depressive patients [18,19]. Recent data support the notion that sleep is a distinct behavioral state but is rather characterized by defined cellular processes, as shown by monitoring sleep or wake associated cortical gene expression at a global scale [21,22], and by progress in attributing sleep associated brain oscillations, i.e. in the theta or delta range, to functions in higher order neuronal plasticity [20,23]
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