The role of serotonin in neuronal function and development
An appreciation of the roles of serotonin as a neurotransmitter and in neuronal growth, particularly during early development, reveals why perturbations in the serotonin signalling systems could contribute to the development of ASD. The serotonergic system is one of the most widely distributed and one of the earliest to develop in the mammalian embryo [58].
In the brain, the majority of serotonergic neurons are located in the median and dorsal raphe nuclei, which project to the cortex or hippocampus, respectively. The cell bodies of the serotonergic neurons are found in clusters, most of which are located in the raphe nuclei of the midbrain, pons and medulla [59]. The serotonergic system innervates virtually all areas of the brain and serotonergic neurons can be detected in the human brain from the fifth gestational week, where they grow and rapidly multiply [60].
With regards to the control of behaviour the two most important clusters of serotonergic neurons are found in the dorsal and medial raphe nuclei, both of which send neuronal projections to the cerebral cortex. As well as its role as a neurotransmitter, serotonin acts as a trophic or differentiation factor in early neurogenesis, where changes in serotonin levels during brain development have been reported to alter neuronal differentiation [61,62].
SERT is a significant contributor to moderating neuronal serotonin levels. There are a significant number of internal and external influences that can alter SERT expression and function from early embryonic stages through to adolescence. And although these influences continue to guide SERT expression and activity throughout adulthood, SERT activity during early periods of human development appear to be vital for guaranteeing normal development [63]. In rodent studies, decreased or increased brain serotonin during the postnatal period of development results in the disruption of synaptic connectivity in sensory cortices in the brain [64-66]. In human studies, serotonin has been demonstrated to be important for prenatal and postnatal brain development [67]. Irregularities in brain serotonin levels can cause asymmetric development of the serotonergic system which leads to incorrectly connecting neural circuits [68]. Changes in serotonergic function and signalling have been found to be associated with ASD [67]. Humans undergo a period of high brain-serotonin synthesis capacity during childhood, a process affected in autistic children [69]. In humans, serotonin activity as measured by the cerebrospinal fluid (CSF) levels of the metabolite 5-HIAA, is higher in children when compared to adults [70,71]. 5HIAA levels in the CSF of children with ASD has been reported to provide a reliable measurement of neural serotonin turnover [14]; however, many studies have indicated a reduction or no change in CSF 5HIAA levels in individuals diagnosed with autistic disorders [72,73]. As such, the levels of serotonin metabolites present in the CSF of ASD-diagnosed individuals is still not firmly established, nor is the impact of blood serotonin levels and how they relate to brain serotonin levels [68].
Functional neuro-imaging studies using positron emission tomography (PET) have shown diminished serotonin synthesis in children with ASD between the age of 2 and 5 years [69]. The short-term depletion of L-tryptophan has been shown to exacerbate repetitive behaviour and elevate anxiety in autistic individuals [74], and drug treatment with selective serotonin re-uptake inhibitors, which interact with SERT, have been shown to be effective in decreasing repetitive and/or obsessive behaviour in some but not all autistic individuals [75].
The main issue with the studies investigating 5HIAA levels in the CSF, platelet serotonin or neuronal serotonin synthesis is that they are completed in cohorts of individuals diagnosed with ASD at different ages and growth stages. The role of serotonin in neuronal development changes throughout infancy and childhood as do the environmental factors that can alter serotonergic systems and function.