Abstract
Many pregnant women experience symptoms of depression, and are often treated with selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine. In utero exposure to SSRIs and maternal depressive symptoms is associated with sex-specific effects on the brain and behavior. However, knowledge about the neurobiological mechanisms underlying these sex differences is limited. In addition, most animal research into developmental SSRI exposure neglects the influence of maternal adversity. Therefore, we used a rat model relevant to depression to investigate the molecular effects of perinatal fluoxetine exposure in male and female juvenile offspring. We performed RNA sequencing and targeted DNA methylation analyses on the prefrontal cortex and basolateral amygdala; key regions of the corticolimbic circuit. Perinatal fluoxetine enhanced myelin-related gene expression in the prefrontal cortex, while inhibiting it in the basolateral amygdala. SSRI exposure and maternal adversity interacted to affect expression of genes such as myelin-associated glycoprotein (Mag) and myelin basic protein (Mbp). We speculate that altered myelination reflects altered brain maturation. In addition, these effects are stronger in males than in females, resembling known behavioral outcomes. Finally, Mag and Mbp expression correlated with DNA methylation, highlighting epigenetic regulation as a potential mechanism for developmental fluoxetine-induced changes in myelination.
Original language | English |
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Pages (from-to) | 1620-1632 |
Number of pages | 13 |
Journal | Neuropsychopharmacology |
Volume | 47 |
Early online date | 31 Jan 2022 |
DOIs | |
Publication status | Published - Aug 2022 |
Bibliographical note
Funding Information:JDAO was supported by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska Curie Individual Fellowship under Grant 660152-DEPREG; and a NARSAD young investigator grant under Grant 25206.
Acknowledgements
We thank Judith Swart, Wanda Douwenga, and Christa Reitzema-Klein for their assistance with the early life stress procedure and drug administration. In addition, we thank Wanda Douwenga for performing the qPCR work.