Role of epigenetics on long-lasting behavioral and gene-expression changes following neonate exposure to antidepressants

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ABSTRACT Depression and anxiety are prevalent during pregnancy and commonly treated with serotonin selective reuptake inhibitor (SSRI) antidepressants. These drugs pass freely from mother to placenta and alter the serotonergic homeostasis in the developing fetus. However, serotonin acts as a trophic factor during embryogenesis and plays an important role in structural development of the central nervous system which has led to a number of studies investigating the short and long-term consequences to the fetus. Multiple rodent models have demonstrated that neonate exposure to SSRIs during a developmentally sensitive time frame equivalent to the 3rd trimester of human pregnancy leads to long-lasting behavioral changes associated with anxiety and depression. These behavioral outcomes in the absence of continued exposure to the SSRI suggests a drug-mediated impact on development through an epigenetic mechanism. This study will investigate this assumption through use a novel transgenic mouse that harbors a mutant serotonin transporter that renders the mouse insensitive to many SSRIs while maintaining normal serotonin transporter and homeostasis. Mice will be evaluated for changes in gene expression, epigenetic marks, and behavior just after SSRI treatment and/or as adult animals. The SSRI-insensitive mouse will provide a critical control to eliminate background effects and pinpoint relevant targets that underlie this phenomenon. Identified targets can then be explored in human populations with the intent of providing a clear understanding of risks involved with SSRI- treatment during pregnancy.