Title: The Role of the Serotonergic Neurotransmitter System in the Development and Treatment of Affective Disorders
Description: Serotonin, arising from neurons of the raphe nuclei, is intimately involved in the treatment of depression and anxiety disorders. Serotonin selective reuptake inhibitors (SSRIs) are frontline therapy for both of these conditions, and have well-described behavioral effects in animal models of emotional behavior. Yet, administration of SSRIs during postnatal development produces an opposing phenotype, including increased anxiety- and depression-like and reduced social behaviors. Because the serotonin transporter, the target of these drugs, is expressed primarily in serotonergic neurons of the raphe, I sought to identify biological mechanisms for behavioral effects of both adult and postnatal SSRI treatment in this cell population. Initially, we compared the transcriptome of serotonergic neurons to whole brain homogenate, in order to both validate the experimental methods, and to provide a descriptive analysis of gene expression in this neuron type. Many transcripts were enriched in raphé samples, including both known markers of serotonergic neurons, and novel genes, most of which could be confirmed from by in situ hybridization data from the Allen Brain Atlas.

In postnatal fluoxetine treated mice, we report alterations at the anatomical, electrophysiological, and transcriptional levels. Serotonergic innervation of the prefrontal cortex and hippocampus was reduced by fluoxetine treatment, consistent with the neurodevelopmental role serotonin plays. The firing rate of serotonergic neurons was also reduced due to an increase in inhibitory transmission. Additionally, the transcriptome of serotonergic neurons was altered by postnatal SSRI: a preponderance of downregulated transcripts was observed, particularly among genes involved in mitochondrial and ribosomal function. These findings combine to suggest a hypotrophic serotonergic system is produced by postnatal SSRI treatment. Studying the effect of adult treatment with SSRIs, we report a normalization of elevated serotonin 1A receptors in depressed, medication-naive patients. However, we did not detect a relationship with clinical response, raising the possibility that serotonin 1A downregulation is an epiphenomenon of SSRI treatment.

In adult fluoxetine treated mice, gene expression profiling identified a number of differentially regulated transcripts. We further used postnatal fluoxetine treatment as a model of treatment resistance, investigating the transcriptional actions of adult fluoxetine treatment in postnatal fluoxetine- vs. saline-treated mice, in order to identify transcripts that track with behavior. We found upregulation of a number of promising candidate genes, including vesicular glutamate transporter 3, histamine receptor 2, and the neuropeptide processing enzyme Ece2.