The serotonin transporter (SERT) is a critical regulator of emotional function that acts both during brain development as a growth modulator and as a neurotransmitter in the more mature brain. It is the primary molecular target for many antidepressants, especially the serotonin selective reuptake inhibitors (SSRIs), which are used as a first- line treatment for a number of psychiatric conditions. SSRIs increase serotonergic tone, and this effect is thought to mediate their therapeutic actions. Paradoxically, genetically reduced SERT expression increases the risk for affective- and anxiety-like behaviors in adult humans, primates, and rodents. The abnormal behaviors of genetically-impaired SERT mice are recapitulated by early life exposure to SERT-blocking agents such as fluoxetine, clomipramine, and citalopram. These findings indicate a critical role of serotonin in the maturation of brain systems that modulate emotional function in the adult and suggest a developmental mechanism to explain how low-expressing SERT promoter alleles increase vulnerability to psychiatric disorders. Moreover, these findings suggest that fetal exposure to SSRIs during pregnancy or early childhood may increase the risk of psychiatric disorders later in life. In this application, we propose several experiments that increase our understanding of the role serotonin plays in modulating brain development. We examine """"""""critical periods"""""""" of development that are sensitive to SERT inhibition. We define the abnormalities of brain structure, connectivity, and physiology that may underlie the adult abnormalities. We also determine the developmental trajectory of behavioral, anatomical, and physiological abnormalities that arise from brief, early exposure to SERT inhibitors. The resulting knowledge obtained by these studies should lead to a better understanding of how serotonin functions during brain development and help inform the underlying pathophysiology of affective and anxiety disorders that may arise due to developmental perturbations in SERT function. Changes in serotonin may affect the way the brain wires itself together during early life. The goal of this proposal is to understand how inhibition of the serotonin transporter affects brain development and behavior. The results have implications for the use of antidepressants during pregnancy and for understanding how certain gene variants predispose to depression and anxiety disorders.
