Abstract
Autism spectrum disorder (ASD) affects reciprocal social interaction and produces abnormal repetitive, restrictive behaviors and interests. The diverse causes of ASD are divided into genetic alterations and environmental risks. The prevalence of ASD has been rising for several decades, which might be related to environmental risks as it is difficult to consider that the prevalence of genetic disorders related to ASD would increase suddenly. The latter includes (1) exposure to medications, such as valproic acid (VPA) and selective serotonin reuptake inhibitors (SSRIs) (2), maternal complications during pregnancy, including infection and hypertensive disorders of pregnancy, and (3) high parental age. Epidemiological studies have indicated a pathogenetic role of prenatal exposure to VPA and maternal inflammation in the development of ASD. VPA is considered to exert its deleterious effects on the fetal brain through several distinct mechanisms, such as alterations of γ-aminobutyric acid signaling, the inhibition of histone deacetylase, the disruption of folic acid metabolism, and the activation of mammalian target of rapamycin. Maternal inflammation that is caused by different stimuli converges on a higher load of proinflammatory cytokines in the fetal brain. Rodent models of maternal exposure to SSRIs generate ASD-like behavior in offspring, but clinical correlations with these preclinical findings are inconclusive. Hypertensive disorders of pregnancy and advanced parental age increase the risk of ASD in humans, but the mechanisms have been poorly investigated in animal models. Evidence of the mechanisms by which environmental factors are related to ASD is discussed, which may contribute to the development of preventive and therapeutic interventions for ASD.
Highlights
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with two symptomatic domains: impairments in reciprocal social interaction and repetitive and restrictive behaviors and interests [1]
Considering that P1 in rats corresponds to approximately 23 weeks gestation in humans, and P8 around delivery [101], these findings suggest that mid-gestational exposure to valproic acid (VPA) produces excitatorydominant E/I imbalance by blocking the excitatory-to-inhibitory shift of GABAergic signaling or reducing vesicular GABA transporter (VGAT) expression and decreasing GABA synthesis in the postnatal brain
We discussed the various contributions of environmental risk factors to the development of ASD
Summary
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with two symptomatic domains: impairments in reciprocal social interaction and repetitive and restrictive behaviors and interests [1]. Both mice [40, 53] and rats [54] that were exposed to VPA on E12 exhibited an increase in mTORC1 activity in the brain and ASD-like behaviors, such as a decrease in social interaction and increase in self-grooming [40, 53, 54]. Fluoxetine administration in mice that began before pregnancy or from early gestation to late-gestation or delivery produced ASD-like behavioral deficits in offspring, decreased USVs in pups, disrupted social interaction, enhanced social dominance, and increased tactile hypersensitivity [135,136,137].
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