Multiple neurotransmitters are involved in different aspects of the melatonin system. The upstream neurotransmitters include serotonin (5-HT) and other related proteases, reflecting the influences of melatonin synthesis abnormality in ASD. Also, gene variation can affect some upstream neurotransmitters in the upstream. Meanwhile, 6-hydroxymelatonin, one downstream metabolite, is widely used to detect for melatonin in clinics. Abnormal release patterns and concentrations of melatonin, along with a disturbing cell signaling network, collectively make patients face the risk factors of ASD. This complex process is often affected by the environment [33], heredity [34], maternal melatonin levels [35], synthesis, and metabolic pathways [36]. New insights into these associations could, therefore, greatly benefit ASD patients [29,[37], [38], [39], [40], [41]]. Two polymorphisms of the acetylserotonin O-methyltransferase (ASMT) gene located in the promoter (rs4446909 and rs5989681) are frequently recognized to be associated with a substantial reduction in melatonin levels in ASD patients [42,43]. In addition, markedly slow nocturnal urinary excretion of 6-sulfate melatonin (6-SM) was observed in ASD patients [39]. Mounting evidence in the researches reveals that melatonin or melatonin receptor agonists can also be leveraged to reverse a set of symptoms other than circadian rhythm disorder and sleep problems. Melatonin reduces and reverses the decreases of hippocampal protein serine/threonine kinases and long-term potentiation (LTP) in the hippocampus in the animal model of autism [44]. In addition, a melatonin receptor agonist can effectively treat insomnia and behavioral symptoms in ASD [45], which attenuates nitrosative stress and inflammation in autism [46].

Uncovering the pathological mechanisms and altered neurobiology of individuals with ASD will lead to innovative therapeutic methods. This review is dedicated to finding possible links between autism and disorders of the melatonin system based on mechanisms that are already recognized.

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