Developmental Perspectives on Serotonin And susceptibility to Mood and Anxiety Disorders
Open Access
- Author:
- Altieri, Stefanie Camille
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- February 08, 2013
- Committee Members:
- Dr Anne M Andrews / David J Vandenbergh, Dissertation Advisor/Co-Advisor
David John Vandenbergh, Committee Chair/Co-Chair
Sonia Angele Cavigelli, Committee Member
Sheri A. Berenbaum, Committee Member - Keywords:
- serotonin
serotonin transporter
antidepressant
development
mood and anxiety
brain-derived neurotrophic factor - Abstract:
- Evidence for the involvement of the serotonin neurotransmitter system in the etiology and treatment of mood and anxiety disorders has accumulated over the past three decades. Developmental influences of serotonin have been forthcoming in putting into perspective how alterations early in life can modify the trajectory of serotonergic circuitry involved in establishing adulthood emotionality. Studies presented in this thesis focused on investigating early life alterations in the function of the serotonin transporter (SERT), the substrate for current antidepressant treatments, using pharmacological and genetic mouse models. These studies provide information that is clinically relevant to antidepressant exposure during pregnancy and human SERT gene polymorphisms, respectively. Mice exposed to the serotonin-selective reuptake inhibitor (SSRI) antidepressants S-citalopram (S-CIT) and fluoxetine (FLX) during a critical postnatal development window and mice with constitutive SERT deletions were compared in terms of emotion-related behavior, physiology, and neurochemistry during late adolescence or adulthood. Findings indicate that postnatal administration of S-CIT but not FLX resulted in reduced anxiety, potentiated 5-HT1A autoreceptor responses, and reductions in extracellular serotonin levels in late adolescent and adult mice. By contrast, lifelong SERT deficiency was associated with increased anxiety, blunted 5-HT1A responses, and increased levels of extracellular serotonin at all ages examined. From these findings, it can be concluded that these two models of early SERT disruption produce dissimilar outcomes and warrant attention to determine the benefits and risks associated with the safety of antidepressants during pregnancy versus untreated maternal depression. Additionally, real-time quantitative PCR assays to determine mRNA levels of genes relevant to mood and anxiety disorders were developed and carried out. In the first study, brain-derived neurotrophic factor (BDNF), a complex gene associated with mechanisms of stress and antidepressant treatment, was studied in SERT-deficient mice. In the mouse, the Bdnf gene contains up to nine splice variants, all encoding the same mature protein, that can be differentially regulated by stress and/or antidepressant therapies. Findings show that SERT-deficient mice having increased anxiety and hypersensitivity to stress show reductions in total BDNF levels, as well as levels of splice variants containing Exons I and V. A second study to investigate SERT expression in rhesus macaques with respect to a SERT gene polymorphism (5 HTTLPR) associated with enhanced anxiety traits in carriers of the short allele of this polymorphism was undertaken. Although functional changes in SERT (reductions in uptake) were observed with respect to short allele carriers, these changes were correlated with surface SERT expression but not SERT mRNA levels. Together, these studies suggest that while the serotonin neurotransmitter system is undoubtedly involved in the pathophysiology and treatment of emotional disorders, many complexities and questions remain to be addressed. Nonetheless, understanding developmental roles of serotonin provide a means to gain a better understanding as changes occurring during this period are sufficient to generate persistent alterations in serotonergic circuitry.