Impact of early-life serotonin dysregulation on cortical interneuron development

Early-life deficiency of the serotonin transporter (SERT) gives rise to a wide range of psychiatric-relevant phenotypes. Among the targets of early-life serotonin, the serotonin receptor 3A (5-HT3AR) specifically controls the embryonic migration and postnatal cortical laminar positioning of caudal ganglionic eminence (CGE) derived cortical interneurons (cINs). Here we investigated the impact of early-life SERT deficiency on the migration and positioning of CGE-derived cortical INs in SERT-ko mice and in mice exposed to the SERT inhibitor fluoxetine during the late embryonic period using microarray-based expression analysis and confocal imaging. We further aimed to identify the genetic programs that control the diversity of 5-HT3AR-expressing interneurons using single-cell RNA sequencing. Postnatal studies revealed that SERT-deficiency affects the cortical laminar distribution of specific CGE-derived interneuron. Preliminary single-cell results indicate that the combinatorial expression of transcription factors Nr2f2 and Sp8 may be a promising method to start re-classifying 5-HT3AR-expressing IN subtypes into biologically relevant subgroups.