SSRIs target prefrontal to raphe circuits during development modulating synaptic connectivity and emotional behavior

OLUSAKIN J; CHEN X; SZE JY; SOIZA-REILLY M; TELLEY L; MAMELI M; GASPAR P; MEYE FJ; PETIT E; JABAUDON D

MOLECULAR PSYCHIATRY

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2019 vol. 24 p. 726 - 745

1359-4184

Antidepressants that block the serotonin transporter (Slc6a4/SERT), selective serotoninreuptake inhibitors (SSRIs) improve mood in adults but have paradoxical long-termeffects when administered during perinatal periods, increasing the risk to developanxiety and depression. The basis for this developmental effect is not known. Here, weshow that during an early postnatal period in mice (P0-P10), Slc6a4/SERT is transientlyexpressed in 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 of PFCSlc6a4/SERT expression. Complete or cortex-specific ablation of SERT increases thenumber of functional PFC glutamate synapses on both 5-HT and GABA neurons in theDRN. This PFC-to-DRN hyper-innervation is replicated by early life exposure to theSSRI, fluoxetine (from P2 to P14) that also causes anxiety/depressive-like symptoms.We show that pharmacogenetic manipulation of PFC-SERT+ neuron activitybidirectionally modulates these symptoms, suggesting that PFC hypo-functionality has acausal role. Overall, our data identify specific PFC descending circuits that are targets ofantidepressant drugs during development. We demonstrate that developmentalexpression of SERT in this subset of PFC neurons controls synaptic maturation of PFCto-DRN circuits, and that remodeling of these circuits in early life modulates behavioralresponses to stress in adulthood.