Melatonin as a Novel Interventional Candidate for Fragile X Syndrome with Autism Spectrum Disorder in Humans

Abstract

Fragile X syndrome (FXS) is the most common monogenic form of autism spectrum disorder (ASD). FXS with ASD results from the loss of fragile X mental retardation (fmr) gene products, including fragile X mental retardation protein (FMRP), which triggers a variety of physiological and behavioral abnormalities. This disorder is also correlated with clock components underlying behavioral circadian rhythms and, thus, a mutation of the fmr gene can result in disturbed sleep patterns and altered circadian rhythms. As a result, FXS with ASD individuals may experience dysregulation of melatonin synthesis and alterations in melatonin-dependent signaling pathways that can impair vigilance, learning, and memory abilities, and may be linked to autistic behaviors such as abnormal anxiety responses. Although a wide variety of possible causes, symptoms, and clinical features of ASD have been studied, the correlation between altered circadian rhythms and FXS with ASD has yet to be extensively investigated. Recent studies have highlighted the impact of melatonin on the nervous, immune, and metabolic systems and, even though the utilization of melatonin for sleep dysfunctions in ASD has been considered in clinical research, future studies should investigate its neuroprotective role during the developmental period in individuals with ASD. Thus, the present review focuses on the regulatory circuits involved in the dysregulation of melatonin and disruptions in the circadian system in individuals with FXS with ASD. Additionally, the neuroprotective effects of melatonin intervention therapies, including improvements in neuroplasticity and physical capabilities, are discussed and the molecular mechanisms underlying this disorder are reviewed. The authors suggest that melatonin may be a useful treatment for FXS with ASD in terms of alleviating the adverse effects of variations in the circadian rhythm.

Impaired GABA Neural Circuits Are Critical for Fragile X Syndrome

“…Clinical studies have illustrated that melatonin-dependent signaling pathways can impair vigilance, learning, and memory abilities and may be linked to autistic behaviors such as abnormal anxiety responses [ 69 , 70 ]. Low melatonin levels are related with altered GABAergic system [ 71 ].…”

The Relationship between Autism Spectrum Disorder and Melatonin during Fetal Development

“…ASD refers to the range of neurodevelopmental disorders accompanying impairments in social interaction, difficulties in communication, and stereotyped or repetitive behaviors. Because the symptoms of autism vary enormously, the term "autism spectrum disorder" encompasses a single diagnostic category of autism involving numerous conditions [34]. Whereas the older term, autism, described a specific diagnostic category, the newer term, ASD, better explains this disorder by including multiple conditions [34].…”

“…Because the symptoms of autism vary enormously, the term "autism spectrum disorder" encompasses a single diagnostic category of autism involving numerous conditions [34]. Whereas the older term, autism, described a specific diagnostic category, the newer term, ASD, better explains this disorder by including multiple conditions [34]. In this regard, the older term is being replaced by the newer term ASD.…”

“…Genetic disruption may give rise to synaptic deficits, and ultimately cause ASD. It has been revealed that ASD-related genes are involved in common signal transduction pathways that are responsible for synaptic development and neuronal plasticity [34].…”

“…Additionally, the mutation of this gene disrupts the normal sleep pattern and circadian rhythm. Subsequent alterations of melatonin synthesis and melatonin-dependent pathways may lead to autistic behaviors [34]. Melatonin is a well-known modulator of the regulation of neural plasticity and circadian rhythm [38,39].…”