Serotonin in the Frontal Cortex: A Potential Therapeutic Target for Neurological Disorders

Abstract

Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter which has broad distribution in the brain. It was discovered by Erspamer and Asero in the 1950s [1]. 5-HT is synthesized in two steps, with Tryptophan Hydroxylase (TPH) as the rate-limiting enzyme [2]. First, tryptophan is converted to 5-hydroxytryptophan (5-HTP) by TPH. Second, the intermediate product, 5-HTP, is converted to 5-HT by aromatic acid decarboxylase (AADC). 5-HT is primarily degraded by the mitochondrial bound protein Monoamine Oxidase A (MAOA), leading to the generation of the metabolite, 5-hydroxyindoleacetic acid (5-HIAA). Importantly, serotonin is also a substrate for melatonin synthesis [3]. 5-HT is released from the axonal terminals of serotoninergic neurons and acts on 14 distinct receptor subtypes that are classified into 7 different families: 5-HT1 (1A, 1B, 1D, 1E, 1F), 5-HT2 (2A, 2B, and 2C), 5-HT3, 5-HT4, 5-HT5 (5A, 5B), 5-HT6, and 5-HT7. Among all these receptors, only 5-HT3 receptor is a pentameric ligand-gated ion channel composed of several subunits of which 5 different types have been identified [4]. All other 5-HT receptors are G-protein coupled receptors which regulate the activity of the neurons expressing them [5,6]. Released serotonin is transported to the presynaptic neurons by serotonin transporter (SERT or 5-HTT), a type of monoamine transporter protein [7]. Serotonergic neurons are located in the raphe nuclei [8]. While the more caudal raphe nuclei project to the Peripheral Nervous System (PNS), the neurons in the dorsal and median raphe nuclei (DRN and MRN) primarily send their projections to forebrain regions [9,10]. 5-HT is critically involved in the development of many cortices, such as somatosensory cortex and barrel cortex [11,12]. In adult brain, 5-HT neurons project to majority of cortical areas, including the entorhinal and cingulate cortices. However, of all cortical regions, the frontal lobe contains the highest density of serotonergic terminals and 5-HT receptors [13]. These studies indicate that 5-HT regulates cognitive and emotional functions that rely on frontal cortical activity.