CONICET | Buscador de Institutos y Recursos Humanos

Themedial prefrontal cortex (mPFC) plays a major role in emotional control, alarge part of which appears to be mediated by feedback connections to brainstemmonoaminergic neurons, in particular to serotoninergic neurons in the dorsal raphenucleus (DRN). Thus, alterations in the developmental trajectory of theseneurons could play an important role in the psychopathology of anxiety-depressivedisorders. Werecently determined that PFC-to raphe neural circuits transiently express SLC6A4, the gene encoding the monoamine serotonintransporter (SERT) that ensures high affinity reuptake of 5-HT, and is the majortarget of antidepressants. We demonstrated that subsets of layer 5-6 pyramidal inthe mPFC express SERT from E18- to P10. These neurons establish synaptic connectionswith subcortical targets including serotoninergic and GABAergic neurons in theDRN. Complete or cortex specific ablation of SLC6A4, SERT induces an increase excitatorysynaptic input from the PFC onto both 5-HT and GABA neurons in the raphe. This indicated that SERT is cell-autonomouslycontrols the development of PFC-raphe connectivity. To decipher the underlyingmechanisms we are analyzing the postnatal development of the PFC-raphe circuit.This shows that PFC axons reach the raphe by P3 but that terminal innervationcontinues to increase over the first 3 postnatal weeks. Current experiments using in utero electroporationof a synaptic-GFP fusion protein into the SERT+PFC neurons should allowdetermining the onset of synaptogenesis and of the hyperinnervation phenotypein the SERT-KO mice. In parallel we areinvestigating the role of the5-HT7 receptor in this hyper-innervation phenotype. This Gs and G12coupled receptor has been reported to control synapse formation. It shows apeak of expression during the period of PFC SERT expression and isdown-regulated in the PFC of SERT-KO mice. Overall our findings indicate a critical roleof SERT in the postnatal period for the maturation of PFC-raphe circuits andsuggest that a tight control of 5-HT receptor activation could be key incontrolling synapse numbers in PFC targets.