Date of Award
Doctor of Philosophy (PhD)
L. Keith Henry
Perinatal depression is a complex mood disorder often treated with Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants, which block the serotonin transporter (SERT) and alter synaptic serotonin concentrations. The serotonergic system is highly plastic and serotonin regulates the growth and maturation of neurons and signaling systems from conception through end of life. Notably, interference with serotonin levels during an SSRI sensitive window (SSW) of development in humans and rodents has been linked to neurovegetative effects which increase susceptibility for the manifestation of anxiety- and depressive-like behaviors and can be persistent throughout life. We hypothesize the persistent behavioral perturbations resulting from acute SSRI challenge during the SSW are the culmination of gene expression changes altering epigenetic modifications in the genome. Historically, inferences have been drawn from comparing postnatal SSRI treated wild- type (WT) mice to those that lack a functioning SERT. This model is problematic, as SERT knock-out (KO) mice display numerous physiological deficits prior to the SSW due to the trophic developmental role of serotonin. In this study, we attempt to characterize a more appropriate mouse model by utilizing RNA-Seq analysis to compare midbrain and hippocampus transcriptomes of WT and KO mice to the transgenic SERT I172M mouse that harbors a fully functioning transporter while rendering SERT resistant to many SSRIs. We further characterized pertinent metabolites to determine brain levels, and if I172M selectivity was maintained and revealed, desmethylcitalopram accumulates in the brain over time and not all SSRI metabolites maintain I172M selectivity. The primary focus of this study was the transcriptomic characterization of the I172M mouse, which is necessary before beginning postnatal SSRI treatment studies. Overall our findings unveil KO mice have significant aberrant neuronal signaling and neurotransmitter metabolism. Moreover, KO mice display dysregulated protein and RNA processing due to midbrain aggregation of misfolded truncated SERT protein and ectopic hippocampal Sert mRNA expression, respectively. Interestingly, comparison of differentially expressed genes in the midbrain and hippocampus of WT/I172M and WT/KO revealed that the Sert locus may share expression quantitative trait loci with Neurexin 1 (Nrxn1) and the transcription factor D- Box Binding PAR BZIP (Dbp), which is independent of Sert expression. Collectively, our data demonstrate WT and I172M mice share similar transcriptomes and validate the ability of the I172M model, over SERT KO, to appropriately detect SERT-SSRI mediated versus non-SSRI SERT mediated changes in response to postnatal SSRI exposure.
Rodriquez, Meghan Alicia, "Transcriptomic And Pharmacological Characterization Of A Murine Line Harboring An Antidepressant-Insensitive Serotonin Transporter" (2021). Theses and Dissertations. 4097.