Disruption of circadian rhythm and risk of autism spectrum disorder: role of immune-inflammatory, oxidative stress, metabolic and neurotransmitter pathways

Abstract

Circadian rhythms in most living organisms are regulated by light and synchronized to an endogenous biological clock. The circadian clock machinery is also critically involved in regulating and fine-tuning neurodevelopmental processes. Circadian disruption during embryonic development can impair crucial phases of neurodevelopment. This can contribute to neurodevelopmental disorders like autism spectrum disorder (ASD) in the offspring. Increasing evidence from studies showing abnormalities in sleep and melatonin as well as genetic and epigenetic changes in the core elements of the circadian pathway indicate a pivotal role of circadian disruption in ASD. However, the underlying mechanistic basis through which the circadian pathways influence the risk and progression of ASD are yet to be fully discerned. Well-recognized mechanistic pathways in ASD include altered immune-inflammatory, nitro oxidative stress, neurotransmission and synaptic plasticity, and metabolic pathways. Notably, all these pathways are under the control of the circadian clock. It is thus likely that a disrupted circadian clock will affect the functioning of these pathways. Herein, we highlight the possible mechanisms through which aberrations in the circadian clock might affect immune-inflammatory, nitro-oxidative, metabolic pathways, and neurotransmission, thereby driving the neurobiological sequelae leading to ASD.

Role of Melatonin in the Management of Sleep and Circadian Disorders in the Context of Psychiatric Illness

“…Especially, abnormalities in the sense of time, which are hypothesized as "temporal binding deficit" or "social timing hypothesis," were observed in high-functioning autism patients as well as in severely symptomatic patients [31•]. Furthermore, disruption of circadian rhythms might affect immune-inflammatory, oxidative, and metabolic pathways, as well as neurotransmission underlying the biological mechanisms of autism [8].…”

“…Melatonin is a key hormone regulating both sleep and circadian rhythms [6]. In psychiatric disorders, abnormalities of melatonin secretion and regulation have been reported [7,8]. These might be due to either decreased secretion from the This article is part of the Topical Collection on Sleep Disorders pineal gland, or dysregulation of the secretion due to internal or external reasons [9,10].…”

Burden of insomnia on healthcare utilization in children with autism spectrum disorder

“…Some studies have proposed possible mechanistic explanations for the increased presence of comorbid disorders in individuals with insomnia including circadian rhythm misalignment (Nobre, Rocha, Morin, & Meira e Cruz, 2021), a low-grade inflammatory state (Friedman, 2011), elevation of cortisol (Vargas et al, 2018), and metabolic or endocrine changes (Copinschi, 2005). Some of these mechanisms were also suggested to be involved in ASD etiology (Abdul et al, 2022;Geoffray, Nicolas, Speranza, & Georgieff, 2016), thus highlighting potential mechanistic links between ASD and insomnia.…”

Neurotransmitters—Key Factors in Neurological and Neurodegenerative Disorders of the Central Nervous System

“…Abnormalities in monoamine NTs have also been correlated with ASD. Impaired dopamine, norepinephrine, and serotonin homeostasis are reflected in altered sleep patterns, mood, and the behavior of ASD patients [ 97 , 101 ]. Particularly, reduced dopamine release in the prefrontal cortex and reduced neural response in the nucleus accumbens have been observed in autistic subjects [ 96 ].…”