Fluoxetine and citalopram significantly alter gene expression in the midbrain of neonate mice uncovering possible antidepressant‐mediated epigenetic programming changes during development.

Abstract

Selective serotonin (5‐HT) reuptake inhibitors (SSRIs) are the primary medication prescribed for depression during pregnancy and act by increasing serotonergic tone via binding and inhibiting 5‐HT reuptake by the serotonin transporter (SERT). In utero exposure to SSRIs has been linked to developmental delays and malformations and could be related to the trophic actions of 5‐HT. In longitudinal studies, in utero exposure to SSRIs in humans has been associated with increased mood disorder diagnoses in adults. Similar findings have been observed in rodent models where neonate treatment with SSRIs results in depressive and anxiety‐like behaviors in adult animals. These models exploit specific developmental windows when the brain has increased susceptibility to changes in serotonergic tone. Early‐life challenge by SSRIs and long‐term behavioral consequences implicates the involvement of epigenetic mechanisms. To investigate this possibility, RNA‐Seq analysis was performed on midbrain, cortex and hippocampal tissue from neonate mice challenged with the SSRIs fluoxetine (FLX), citalopram (CIT) or paroxetine (PXT) from postnatal days (PND) 4–21 and 4–28. In midbrain samples, FLX‐treated PND 4–21 mice had 43 differentially expressed genes (DEGs), whereas CIT‐ treated PND 4–28 mice had 193 DEGs. These results were encouraging, as the midbrain is enriched with serotonergic cell bodies in the raphe nuclei. In contrast, gene expression changes were not identified in cortex or hippocampal tissues which contain serotonergic termini and an increased heterogeneous cell population in comparison to the midbrain. This heterogeneity presents significant challenges for detecting SSRI‐mediated changes in gene expression. Pathway analysis revealed an enrichment of transcripts associated with serotonergic and dopaminergic signaling, and with multiple cellular functions involved in neuronal communication and nervous system development in the midbrain of CIT and FLX‐treated mice. Importantly, several key genes involved in epigenetic modifications, such as histone acetylation and methylation of RNA, mRNA and histones were differentially expressed in CIT‐treated mice, implicating a link to epigenetic mechanisms. Additionally, neonate treatment with CIT affects ribosome function and mRNA splicing and processing. Collectively, these data provide reasonable candidate genes which can be evaluated for a role in SSRI‐mediated developmental changes in the brain and how these alterations can lead to persistent behavioral changes in adult animals.Support or Funding InformationNIH‐NIGMS P20 GM104360This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.