Genetic and pharmacological manipulations of the serotonergic system in early life: neurodevelopmental underpinnings of autism-related behavior

Abstract

Serotonin, in its function as neurotransmitter, is well-known for its role in depression, autism and other neuropsychiatric disorders, however, less known as a neurodevelopmental factor. The serotonergic system is one of the earliest to develop during embryogenesis and early changes in serotonin levels can have large consequences for the correct development of specific brain areas. The regulation and functioning of serotonin is influenced by genetic risk factors, such as the serotonin transporter polymorphism in humans. This polymorphism is associated with anxiety-related symptoms, changes in social behavior, and cortical gray and white matter changes also seen in patients suffering from autism spectrum disorders (ASD). The human polymorphism can be mimicked by the knockout of the serotonin transporter in rodents, which are as a model system therefore vital to explore the precise neurobiological mechanisms. Moreover, there are pharmacological challenges influencing serotonin in early life, like prenatal/neonatal exposure to selective serotonin reuptake inhibitors (SSRI) in depressed pregnant women. There is accumulating evidence that this dysregulation of serotonin during critical phases of brain development can lead to ASD-related symptoms in children, and reduced social behavior and increased anxiety in rodents. Furthermore, prenatal valproic acid (VPA) exposure, a mood stabilizing drug which is also thought to interfere with serotonin levels, has the potency to induce ASD-like symptoms and to affect the development of the serotonergic system. Here, we review and compare the neurodevelopmental and behavioral consequences of serotonin transporter gene variation, and prenatal SSRI and VPA exposure in the context of ASD.

Sculpting Cerebral Cortex with Serotonin in Rodent and Primate

“…Later, it was shown that genetic SERT deficiency affected S1 organization similarly in rodent. These alterations are not only structural but also impair whisker-mediated perception [10]. Hyper-activation of the 5-HT 1B receptor, transiently expressed on TCAs during development, plays a key role in this process.…”

“…Developmental perturbations impacting the maturation of cortical circuits can trigger neuropsychiatric disorders [8][9][10]. Sensitive periods or windows of vulnerability have been demonstrated in various processes in particular for the rodent sensory systems as well as in the modulation of complex behaviours.…”

“…Not surprisingly, like in non-mammalian species, serotonin modulates neuronal proliferation, migration and differentiation. In addition, 5-HT is implicated in the emergence of many neuropsychiatric disorders, including mental retardation, autism, depression and anxiety [10,15,[21][22][23][24][25][26]. Importantly, 5-HT signalling is influenced by numerous epigenetic and genetic factors, including nutrition and gut microbiota [27,28], perinatal stress [29][30][31], infection and inflammation [32][33][34][35], 5-HT metabolism and storage [15,[36][37][38], pharmacological compounds such as selective serotonin reuptake inhibitors [38][39][40] and genetic alterations [41][42][43][44].…”

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

“…These drugs are able to modulate the expression of many genes involved in processes such as proliferation, apoptosis, neuronal differentiation and migration, synaptogenesis, and synaptic activity [229]. Exposure to selective serotonin reuptake inhibitors (SSRI) in depressed pregnant women might be involved in the etiology of autism, as well as the prenatal valproic acid (VPA) exposure, which is also thought to interfere with serotonin levels [230], by disruption of early serotonergic neuronal development [231] or via the reduction of PTEN level [232].…”

Links between serotonin reuptake inhibition during pregnancy and neurodevelopmental delay/spectrum disorders: A systematic review of epidemiological and physiological evidence

“…Finally published animal studies consistently show that pups born to animals administered antidepressants during pregnancy show a range of behavioral changes indicative of reduced social confidence and communication deficits consistent with a diagnosis of neurodevelopmental spectrum disorders in humans [54][55][56][57][58][59][60][61].…”