Serotonin-mediated Epigenetic Regulation in the Mouse Prefrontal Cortex during Early Postnatal Life

Psychiatric disorders, including anxiety and depression, may have neurodevelopmental origins, yet the molecular mechanisms underlying vulnerability remain poorly understood. The serotonin (5-HT) system is essential for proper neuronal circuit development during early brain development. Serotonylation, a novel post-translational modification in which 5-HT is attached to protein glutamine residues, may link serotonin signaling to gene regulation. In histone H3, serotonylation occurs at glutamine 5 within H3K4me3-marked nucleosomes (H3K4me3Q5ser) and promotes transcription. We study whether this mechanism contributes to the developmental programming of prefrontal cortical circuits underlying emotional vulnerability. Our analyses show that serotonylation is present in the embryonic forebrain and associated with promoters of genes involved in neurodevelopmental processes. In a mouse model of early-life emotional vulnerability with reduced 5-HT in prefrontal neurons, decreased serotonylation is associated with altered expression of gene networks related to axon development and synaptic maturation. ChIP-qPCR experiments corroborate these findings in our model. Further, RNA-seq analyses reveal differential expression in multiple pathways involved in neuronal circuit development. These findings support a role for serotonylation in prefrontal developmental programs that may contribute to adult emotional vulnerability.