Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology. The core syndromes of ASD are deficits in social communication and self-restricted interests and repetitive behaviors. Social communication relies on the proper integration of sensory and motor functions, which is tightly interwoven with the limbic function of reward, motivation, and emotion in the brain. Monoamine neurotransmitters, including serotonin, dopamine, and norepinephrine, are key players in the modulation of neuronal activity. Owing to their broad distribution, the monoamine neurotransmitter systems are well suited to modulate social communication by coordinating sensory, motor, and limbic systems in different brain regions. The complex and diverse functions of monoamine neurotransmission thus render themselves as primary targets of pathophysiological investigation of the etiology of ASD. Clinical studies have reported that children with maternal exposure to valproic acid (VPA) have an increased risk of developing ASD. Extensive animal studies have confirmed that maternal treatments of VPA include ASD-like phenotypes, including impaired social communication and repetitive behavior. Here, given that ASD is a neurodevelopmental disorder, we begin with an overview of the neural development of monoaminergic systems with their neurochemical properties in the brain. We then review and discuss the evidence of human clinical and animal model studies of ASD with a focus on the VPA-induced pathophysiology of monoamine neurotransmitter systems. We also review the potential interactions of microbiota and monoamine neurotransmitter systems in ASD pathophysiology. Widespread and complex changes in monoamine neurotransmitters are detected in the brains of human patients with ASD and validated in animal models. ASD animal models are not only essential to the characterization of pathogenic mechanisms, but also provide a preclinical platform for developing therapeutic approaches to ASD.
Highlights
Autism spectrum disorder (ASD) is a devasting neurodevelopmental disease with an increasing prevalence of ~18.5 per 1000 people [1]
We focus on the valproic acid (VPA)-induced ASD model, because it has been widely adopted to investigate the neuropathophysiology of ASD and used as an experimental platform to develop therapeutic reagents [35,37,68]
Because serotonin transporter (SERT) is critical to 5-HT activity, the kinetics of 5-HT neurotransmission is governed by the level of SERT. 5-HT is metabolically degraded by monoamine oxidase (MAO) and converted into 5-hydrozy-indoleacetaldehyde, which is subsequently oxidized by aldehyde dehydrogenase to derive 5-hydroxyindoleacetic acid (5-HIAA)
Summary
Autism spectrum disorder (ASD) is a devasting neurodevelopmental disease with an increasing prevalence of ~18.5 per 1000 people [1]. The etiology of ASD is highly heterogeneous with genetic and environmental roots. The core syndromes of ASD patients are deficits in social communication/interaction and restrictive/repetitive behavior [2]. Because of its complicated and heterogeneous etiology, the pathological mechanisms are not yet fully characterized, which prevents the development of effective therapy for ASD
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