CONICET | Buscador de Institutos y Recursos Humanos

Selective serotonin reuptake inhibitors (SSRIs)antidepressants that block the serotonin transporter (Slc6a4/SERT) improve moodin adults but have paradoxical long-term effects when administered duringperinatal periods, increasing the risk to develop anxiety and depression. Thebasis for this developmental effect is not known. Here, we show that during anearly postnatal period in mice (P0-P10), Slc6a4/SERT is transiently expressedin a subset of layer 5-6 pyramidal neurons of the prefrontal cortex (PFC).PFC-SERT+ neurons establish glutamatergic synapses with subcortical targets,including the serotonin (5-HT) and GABA neurons of the dorsal raphe nucleus(DRN). PFC-to-DRN circuits develop postnatally, coinciding with the period ofPFC Slc6a4/SERT expression. Complete or cortex-specific ablation of SERTincreases the number of functional PFC glutamate synapses on both 5-HT and GABAneurons in the DRN. This PFC-to-DRN hyper-innervation is replicated by earlylife exposure to the SSRI, fluoxetine (P2 to P14) that also causesanxiety/depressive-like symptoms. We show that silencing the PFC-SERT+ neuronsenhances the emotional alterations caused by early life exposure to SSRIs,increasing passive coping responses. Overall, our data identify specific PFCdescending circuits that are targets of antidepressant drugs duringdevelopment. We demonstrate that developmental expression of rnd that this cicuit ttion of this pathway bya tns with anmine oxidases with clorgyline SERT in this subset of PFC neurons cell-autonomously controlssynaptic maturation of PFC-to-DRN circuits, and that remodeling of thesecircuits in early life modulates behavioral responses to stress in adulthood

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