Prefrontal Serotonin Transporter Shapes Cortico-Raphe Circuits and Long-Term Emotional Deficits of Early-Life Exposure to SSRIs

SOIZA REILLY M

Cordoba

Congreso; 2018 Meeting of Argentine Society for Research in Neurosciences; 2018

Sociedad Argentina de Investigacion en Neurociencias

Loss or reduced function of the serotonin transporter(Slc6a4/SERT) during early development has paradoxicallong-term effects in adult life by increasing vulnerability todepression and anxiety. However, the basis for these developmentaleffects is not known. Here, we show that duringan early postnatal period (P0?P10), Slc6a4/SERT is transientlyexpressed in a subset of Layers 5 to 6 pyramidal neuronsof the prefrontal cortex (PFC). PFC-SERT+ neurons establishglutamatergic synapses with a number of subcorticaltargets, including 5-HT and GABA neurons in the dorsalraphe nucleus (DRN). PFC-to-DRN circuits develop postnatally,coinciding with the period of PFC Slc6a4/SERT expression.Complete or cortex-specific ablation of SERT increasesthe number of functional PFC glutamate synapses onto 5-HTand GABA DRN neurons. This PFC-to-DRN hyper-innervationis replicated by early postnatal exposure to the selectiveserotonin reuptake inhibitor (SSRI) fluoxetine from P2toP14, which also causes long-lasting emotional deficits anddampens the activation of the PFC in response to stress.Targeting the PFC-SERT+ neurons with pharmacogenetictools, we show that chemogenetic inhibition of these neuronsenhances the emotional deficits caused by early lifeexposure to SSRIs. Overall, our data identify specific PFCdescending circuits that are targets of antidepressant drugsduring the perinatal period. We demonstrate that developmentalexpression of SERT in a subset of PFC neurons controlssynaptic maturation of PFC-to-DRN circuits and thatmaladaptive changes of these circuits, induced by early exposureto SSRIs, play a central role in behavioral responsesto stress.