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. 2017 Apr 29;18(5):938.
doi: 10.3390/ijms18050938.

Clock Genes and Altered Sleep-Wake Rhythms: Their Role in the Development of Psychiatric Disorders

Annaëlle Charrier  1 , Bertrand Olliac  2   3 , Pierre Roubertoux  4 , Sylvie Tordjman  5   6
Affiliations

Clock Genes and Altered Sleep-Wake Rhythms: Their Role in the Development of Psychiatric Disorders

Annaëlle Charrier et al. Int J Mol Sci. .

Abstract

In mammals, the circadian clocks network (central and peripheral oscillators) controls circadian rhythms and orchestrates the expression of a range of downstream genes, allowing the organism to anticipate and adapt to environmental changes. Beyond their role in circadian rhythms, several studies have highlighted that circadian clock genes may have a more widespread physiological effect on cognition, mood, and reward-related behaviors. Furthermore, single nucleotide polymorphisms in core circadian clock genes have been associated with psychiatric disorders (such as autism spectrum disorder, schizophrenia, anxiety disorders, major depressive disorder, bipolar disorder, and attention deficit hyperactivity disorder). However, the underlying mechanisms of these associations remain to be ascertained and the cause-effect relationships are not clearly established. The objective of this article is to clarify the role of clock genes and altered sleep-wake rhythms in the development of psychiatric disorders (sleep problems are often observed at early onset of psychiatric disorders). First, the molecular mechanisms of circadian rhythms are described. Then, the relationships between disrupted circadian rhythms, including sleep-wake rhythms, and psychiatric disorders are discussed. Further research may open interesting perspectives with promising avenues for early detection and therapeutic intervention in psychiatric disorders.

Keywords: attention deficit hyperactivity disorder; autism spectrum disorder; circadian clocks network; circadian rhythm; clock genes; mood disorders; psychiatric disorders; schizophrenia; sleep-wake rhythm; synchronization of oscillators.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Model of the mammalian cell-autonomous oscillator (based on Lowrey and Takahashi, 2011) [69]. The transcriptional activators circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1) stimulate the expression of cryptochrome-1 (Cry) and period (Per) genes. The protein products of these genes are associated in the cytoplasm to form dimers that go into the core. There, they serve two functions: first, the repression of their own transcription, via the inhibition of CLOCK–BMAL1; and second, the activation of Bmal1 gene, by a mechanism that remains to be discovered. These proteins are thus two regulating loops, one negative and the other positive. CLOCK and BMAL1 activate also the so-called clock-controlled genes (CCG) whose products transmit the rhythm information to the rest of the body via the output channels of the clock. Some proteins modulate the progression of control loops. Thus, casein kinase Iε (CKIε) can phosphorylate PER proteins, which destabilizes them and prevents their translocation into the nucleus.
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