Effects of antidepressant drug exposure on gene expression in the developing cerebral cortex

Abstract

To clarify the basis of limited responses in children and adolescents to antidepressant treatments considered standard in the treatment of adult major depressive disorder, juvenile Sprague-Dawley rats were subjected to 21-day treatment with dissimilar antidepressant drugs fluoxetine, imipramine, or vehicle control. Total RNA was extracted from brain frontal cortices and hybridized to the Affymetrix 230.2 chip. A total of 18 microarrays were analyzed (i.e., six biological replicates in three treatment groups). Transcripts identified were validated using Taqman real-time quantitative PCR methodology, and the relative expression of each gene was also determined. In both the imipramine- and fluoxetine-treated animals, expression of six genes was down-regulated (ANOVA-filtered gene expression data using dChip [version 2005]): Gpd1; Lrrn3; Sult1A1; Angptl4; Mt1a; Unknown. Furthermore, four genes were over-expressed: P4Ha1; RDG1311476; Rgc32; and SLC25A18-like by both imipramine and fluoxetine. These data demonstrate that antidepressant drugs interfere with the expression of genes involved in cell signaling, survival, and protein metabolism. Our results show that antidepressants regulate the induction of highly specific transcriptional programs in the developing frontal cortex. These findings provide novel insights into the long-term molecular actions of antidepressant drugs in the developing brain.