Extreme enhancement or depletion of serotonin transporter function and serotonin availability in autism spectrum disorder

Abstract

A variety of human and animal studies support the hypothesis that serotonin (5-hydroxytryptamine or 5-HT) system dysfunction is a contributing factor to the development of autism in some patients. However, many questions remain about how developmental manipulation of various components that influence 5-HT signaling (5-HT synthesis, transport, metabolism) persistently impair social behaviors. This review will summarize key aspects of central 5-HT function important for normal brain development, and review evidence implicating perinatal disruptions in 5-HT signaling in the pathophysiology of autism spectrum disorder. We discuss the importance, and relative dearth, of studies that explore the possible correlation to autism in the interactions between important intrinsic and extrinsic factors that may disrupt 5-HT homeostasis during development. In particular, we focus on exposure to 5-HT transport altering mechanisms such as selective serotonin-reuptake inhibitors or genetic polymorphisms in primary or auxiliary transporters of 5-HT, and how they relate to neurological stores of serotonin and its precursors. A deeper understanding of the many mechanisms by which 5-HT signaling can be disrupted, alone and in concert, may contribute to an improved understanding of the etiologies and heterogeneous nature of this disorder. We postulate that extreme bidirectional perturbations of these factors during development likely compound or synergize to facilitate enduring neurochemical changes resulting in insufficient or excessive 5-HT signaling, that could underlie the persistent behavioral characteristics of autism spectrum disorder.

Implication of hypocholesterolemia in autism spectrum disorder and its associated comorbidities: A retrospective case–control study

“…Possible mechanisms regarding the direct effect of low cholesterol have been hypothesized such as a decrease of the serotonin (5HT activity) system activity [Engelberg, ; Scanlon, Williams, & Schloss, ; Steegmans et al, ]. The extreme bidirectional perturbations of the functions of the serotonin transporter have also been investigated in ASD in a variety of animal and human studies [Garbarino, Gilman, Daws, & Gould, ]. Our findings raise the need for further investigations to understand the mechanism through which a low cholesterol contributes to ASD pathophysiology and its associated anxiety/mood disorders.…”

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

“…ASD includes a group of neurodevelopmental disorders characterized by impaired social interaction and communication, repetitive and stereotyped behaviors, often accompanied by intellectual disability [87]. Growing evidence indicate that the brain 5-HT neurotransmission system is altered in ASD patients, and in various animal models of the disease [88][89][90]. For instance, mice lacking brain 5-HT, in addition to several abnormal phenotypes (growth retardation, high aggressive behavior, maternal neglect), show selective deficits resembling ASD's symptoms, including impairments in social interactions and repetitive behavior [3,4].…”

Plasma Levels of Glial Cell Marker S100B in Children With Autism

“…In case of use of S100B as a maker, it has advantages, that it can be detected in different biological fluids, as CSF, blood, saliva, urine, importantly for patients since it can be determined based on noninvasive interventions (Gazzolo et al 2019). The challenge of use of S100B is its concentration dependence on the age (Portela et al 2002), and therefore importance of its comparison to corresponding reference values (Bouvier et al 2011), is crucial for early diagnosis of ASD, what improves the outcomes of interventions (Landa 2018).…”

“…Serotonin participation in autism pathogenesis is suggested, firstly, because augmented blood levels of serotonin have been observed in children with autism, at least in a subgroup of them (25 %) (Marler et al 2016). Secondly, dysregulation of serotonin (increase or decrease) causes behavioral changes, characteristic for autism spectrum disorder (Garbarino et al 2019). Since serotonin has pleiotropic effects, it is hard to specify its role in ASD (for review see (Muller et al 2016, Garbarino et al 2019.…”

“…This molecule is also actively investigated in connection to ASD. Evidence suggests that increased or decreased serotonin level plays a critical role in neurodevelopment (Garbarino et al 2019). The involvement of serotonin in ASD pathomechanisms is widely supported by findings that behavioral symptoms of autism, including deficits in social behavior (Kiser et al 2012) and restrictive repetitive behaviors (Hollander et al 2005), are modulated by 5-HT signaling.…”