The serotonergic system in health and disease

Serotonin is probably best known for its role in conveying a sense of contentedness and happiness. It is one of the most unique and pharmacologically complex monoamines in both the peripheral and central nervous system (CNS). Serotonin has become in focus of interest for the treatment of depression with multiple serotonin-mimetic and modulators of adult neurogenesis used clinically. Here we will take a broad view of serotonin from development to its physiological role as a neurotransmitter and its contribution to homeostasis of the adult rodent hippocampus. This chapter reflects the most significant findings on cellular and molecular mechanisms from neuroscientists in the field over the last two decades. We illustrate the action of serotonin by highlighting basic receptor targeting studies, and how receptors impact brain function. We give an overview of recent genetically modified mouse models that differ in serotonin availability and focus on the role of the monoamine in antidepressant response. We conclude with a synthesis of the most recent data surrounding the role of serotonin in activity and hippocampal neurogenesis. This synopsis sheds light on the mechanisms and potential therapeutic model by which serotonin plays a critical role in the maintenance of mood. Introduction Our knowledge of the biology of serotonin (5-hydroxytryptamine, 5-HT) and its function in the peripheral and CNS has been rapidly growing. This is likely due to the cloning of the multiple receptor subtypes that mediate serotonin signaling and the advent of new technologies to selectively perform gainor loss-of-function studies. In this review we focus on serotonin activity in the rodent brain, and particularly concentrate on the role of serotonin in adult hippocampal neurogenesis. The discovery of newly generated neurons throughout life (Altman and Das, 1965, Kaplan and Hinds, 1977) has not only altered the perception of the general public that the brain lacks the capacity for neuron replacement but also opens novel fields of neuroscience research. Serotonin contributes to this fascination as one of the crucial signals in the neurogenic niche microenvironment together with other growth factors, hormones, or neurotransmitters that regulate cell proliferation and differentiation.