Psychiatric disorders including anxiety and depression affect a large proportion of the human population. Growing evidence indicates that predisposition to develop mental disorders could have neurodevelopmental origins. However, little is known about the molecular and cellular mechanism underlying such phenomenon. The serotonin (5-HT) system and its homeostasis in early life are essential for establishing proper brain circuit architecture and function. Recent studies described a novel post-translational modification called serotonylation, in which a 5-HT molecule is transferred to a protein glutamine residue. In histone H3, such modification occurs at tri-methylated lysine 4 (H3K4me3)-marked nucleosomes (H3K4me3Q5ser) promoting transcription. We study if this regulatory mechanism could have a role in the early vulnerability of prefrontal cortical circuits resulting in adult emotional alterations. Preliminary analyses show that serotonylation is present in the forebrain during embryonic life, mainly regulating promoters of genes involved in specific neurodevelopmental processes across ages. In a mouse model of early-life emotional vulnerability with decreased levels of 5-HT in prefrontal neurons, a decrease in serotonylation levels affects the expression of gene networks involved in axon development and synaptic maturation. Further studies will determine how this may impact on long-standing prefrontal circuit alterations and emotional symptoms in this model.