Background: The alterations in neurological and neuroendocrine functions observed in the autism
spectrum disorder (ASD) involves environmentally dependent dysregulation of neurodevelopment, in interaction
with multiple coding gene defects. Disturbed sleep-wake patterns, as well as abnormal melatonin and glucocorticoid
secretion, show the relevance of an underlying impairment of the circadian timing system to the behavioral
phenotype of ASD. Thus, understanding the mechanisms involved in the circadian dysregulation in ASD could
help to identify early biomarkers to improve the diagnosis and therapeutics as well as providing a significant
impact on the lifelong prognosis.
Objective: In this review, we discuss the organization of the circadian timing system and explore the connection
between neuroanatomic, molecular, and neuroendocrine responses of ASD and its clinical manifestations. Here
we propose interconnections between circadian dysregulation, inflammatory baseline and behavioral changes in
ASD. Taking into account, the high relevancy of melatonin in orchestrating both circadian timing and the maintenance
of physiological immune quiescence, we raise the hypothesis that melatonin or analogs should be considered
as a pharmacological approach to suppress inflammation and circadian misalignment in ASD patients.
Strategy: This review provides a comprehensive update on the state-of-art of studies related to inflammatory
states and ASD with a special focus on the relationship with melatonin and clock genes. The hypothesis raised
above was analyzed according to the published data.
Conclusion: Current evidence supports the existence of associations between ASD to circadian dysregulation,
behavior problems, increased inflammatory levels of cytokines, sleep disorders, as well as reduced circadian
neuroendocrine responses. Indeed, major effects may be related to a low melatonin rhythm. We propose that
maintaining the proper rhythm of the circadian timing system may be helpful to improve the health and to cope
with several behavioral changes observed in ASD subjects.