Biological Timing and Neurodevelopmental Disorders: A Role for Circadian Dysfunction in Autism Spectrum Disorders

Abstract

Autism spectrum disorders (ASDs) are a spectrum of neurodevelopmental disorders characterized by impaired social interaction and communication, as well as stereotyped and repetitive behaviors. ASDs affect nearly 2% of the United States child population and the worldwide prevalence has dramatically increased in recent years. The etiology is not clear but ASD is thought to be caused by a combination of intrinsic and extrinsic factors. Circadian rhythms are the ∼24 h rhythms driven by the endogenous biological clock, and they are found in a variety of physiological processes. Growing evidence from basic and clinical studies suggest that the dysfunction of the circadian timing system may be associated with ASD and its pathogenesis. Here we review the findings that link circadian dysfunctions to ASD in both experimental and clinical studies. We first introduce the organization of the circadian system and ASD. Next, we review physiological indicators of circadian rhythms that are found disrupted in ASD individuals, including sleep-wake cycles, melatonin, cortisol, and serotonin. Finally, we review evidence in epidemiology, human genetics, and biochemistry that indicates underlying associations between circadian regulation and the pathogenesis of ASD. In conclusion, we propose that understanding the functional importance of the circadian clock in normal and aberrant neurodevelopmental processes may provide a novel perspective to tackle ASD, and clinical treatments for ASD individuals should comprise an integrative approach considering the dynamics of daily rhythms in physical, mental, and social processes.

Keywords: autism spectrum disorders; circadian rhythms; clock genes; cortisol; mTOR; melatonin; serotonin; sleep.

FIGURE 1

Transcription-translation feedback loops (TTFLs) in the mammalian circadian clock. The CLOCK and BMAL1 proteins are activators and form a heterodimer to bind to E-box enhancers in the promoters of Per and Cry genes. PER and CRY proteins are synthesized during the day and form a protein complex which accumulates in the cytoplasm during the afternoon and evening. Upon reaching certain level, the PER-CRY complexes translocate into the cell nucleus during the nighttime and block the activities of the CLOCK: BMAL1 heterodimer to inhibit their own gene transcription. In addition, the CLOCK: BMAL1 complex also promotes the transcription of Rev-erb and Ror. REV-ERB in turn inhibits Bmal1 transcription whereas ROR promotes Bmal1 transcription. The abundance of PER proteins is controlled at the level of mRNA translation by rhythmic phosphorylation of eIF4E. Phosphorylation of eIF2α promotes translation of Atf4. ATF4 directly activates Per2 transcription. At the posttranslational level, levels of PER and CRY protein are regulated by phosphorylation and ubiquitination-mediated protein degradation CKI phosphorylates PER. Phosphorylation of PER and CRY proteins promotes their degradation and speeds up the clock.

FIGURE 2

A diagram illustrating key steps involved in photic entrainment of the circadian system. (1) Ambient light stimulates intrinsically photosensitive retinal ganglion cells (ipRGCs) in the retina. (2) The axons of ipRGCs travel via the retinohypothalamic tract (RHT) to form synaptic connections with the core neurons of hypothalamic suprachiasmatic nucleus (SCN). Glutamate and pituitary adenylate cyclase activating polypeptide (PACAP), among other neurotransmitters are released at the synapses of the RHT terminals to the SCN neurons. Synaptic activities induce clock gene expression and reset the SCN clock. (3) SCN sends rhythmic outputs to other brain regions and peripheral oscillators to reset their rhythms.

FIGURE 3

Intrinsic and extrinsic factors that can lead to the pathogenesis of autism spectrum disorders.

FIGURE 4

A pathway of melatonin biosynthesis. Melatonin synthesis is the result of the amino acid tryptophan through the intermediate neurotransmitter serotonin. The conversion of serotonin to melatonin is mediated by two enzymes, serotonin N-acetyl transferase (SNAT) and acetylserotonin O-methyltransferase (ASMT). The protein 14-3-3 mediates both of these stepwise interactions.

FIGURE 5

SCN regulates the hypothalamic-pituitary-adrenocortical axis. Cortisol production is regulated by three steps: (1) Release of corticotropin releasing hormone (CRH) by the hypothalamic paraventricular nucleus (PVN); (2) the adrenocorticotropic hormone (ACTH) is released from the anterior pituitary; and (3) Cortisol is synthesized and released from the adrenal cortex. Cortisol inhibits CRH and ACTH release at a feedback mechanism. The SCN has direct neural inputs into PVN and controls the daily rhythms of cortisol levels.