Ontogeny and regulation of the serotonin transporter: Providing insights into human disorders

Abstract

Serotonin (5-hydroxytryptamine, 5-HT) was one of the first neurotransmitters for which a role in development was identified. Pharmacological and gene knockout studies have revealed a critical role for 5-HT in numerous processes, including cell division, neuronal migration, differentiation and synaptogenesis. An excess in brain 5-HT appears to be mechanistically linked to abnormal brain development, which in turn is associated with neurological disorders. Ambient levels of 5-HT are controlled by a vast orchestra of proteins, including a multiplicity of pre- and post-synaptic 5-HT receptors, heteroreceptors, enzymes and transporters. The 5-HT transporter (SERT, 5-HTT) is arguably the most powerful regulator of ambient extracellular 5-HT. SERT is the high-affinity uptake mechanism for 5-HT and exerts tight control over the strength and duration of serotonergic neurotransmission. Perturbation of its expression level or function has been implicated in many diseases, prominent among them are psychiatric disorders. This review synthesizes existing information on the ontogeny of SERT during embryonic and early postnatal development though adolescence, along with factors that influence its expression and function during these critical developmental windows. We integrate this knowledge to emphasize how inappropriate SERT expression or its dysregulation may be linked to the pathophysiology of psychiatric, cardiovascular and gastrointestinal diseases.

A refined high carbohydrate diet is associated with changes in the serotonin pathway and visceral obesity

“…The complexity of Sert expression and function is not yet fully understood (Daws & Gould, 2011). Nonetheless, given that in vitro studies have shown that long-term exposure to high glucose concentrations further increases the activity of Sert (Goncalves et al, 2008), it is possible that the consumption of refined carbohydrate over an extended time determined the patterns of expression of Sert seen in our investigation.…”

Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

“…Moreover, for several of these variants, their activity cannot be further increased by p38 MAPK activation , suggesting these variants may be constitutively poised in the state normally produced after p38 MAPK activation. Expression of SERT molecules with constitutively elevated 5-HT clearance could drive developmental onset disorders linked to 5-HT such as ASD owing to the early embryonic expression of 5-HT and SERT (Daws and Gould, 2011). Recently, a mouse with a knock-in mutation of the most common of these variants, Ala56, was generated and found to exhibit behavioral perturbations reminiscent of ASD .…”

Structure-Function of Serotonin in Bivalve Molluscs

“…This mechanism results in the inactivation of 5-HT by removing it from the synaptic cleft. Studies have also shown that a 5-HT reuptake inhibitor (SRI) interferes with SERT function to inhibit or suppress 5-HT reuptake [80,81].…”