Genetic Inactivation of the Serotonin Transporter Dysregulates Expression of Neurotransmission Genes and Genome‐Wide DNA Methylation Levels in the Medial Prefrontal Cortex of Male Rats During Postnatal Development

Reduced expression of the serotonin transporter (5-hydroxytryptamine transporter, 5-HTT) in early life has been associated with a delay in postnatal brain development and endophenotypes of a variety of neuropsychiatric and neurodevelopmental disorders in adolescence and adulthood. How a reduction in functional 5-HTT can disrupt neurodevelopment is still largely unknown. Here, we studied genome-wide gene expression using transcriptome analysis (RNA-seq) and global levels of DNA (hydroxy)methylation (5(h)mC) using high-performance liquid chromatography-tandem mass spectrometry in 5-HTT wild-type (5-HTT^+/+) and 5-HTT homozygous knockout (5-HTT^-/-) rats across life (postnatal day [PND] 8, 14, 21, 35, and 70) in the medial prefrontal cortex (mPFC); a brain region with an extensive serotonergic innervation involved in several neuropsychiatric endophenotypes. We observed most gene expression changes in the mPFC during early postnatal life (PND8) and found at this time point an enrichment of genes linked to neuronal and developmental processes like neurotransmission, neuropeptide signaling, and cell migration. Genome-wide DNA 5(h)mC analysis showed a global increase in 5-hydroxymethylcytosine (5hmC) in the mPFC during development in both genotypes and a significant increase in global 5hmC in 5-HTT^-/- compared to 5-HTT^+/+ rats at PND35. The differences in the regulation of gene expression in 5-HTT^-/- versus 5-HTT^+/+ rats during early postnatal life can dysregulate neurodevelopmental processes resulting in aberrant brain wiring and functioning. This can result in lifelong consequences for prefrontal context-dependent executive functioning.