Prefrontal serotonin transporter shapes cortico-raphe circuits and long-term emotional deficits of early-life exposure to SSRIs

SOIZA REILLY M

Cordoba

Congreso; Sociedad Argentina de Investigacion en Neurociencias; 2018

SAN

Loss or reduced function of the serotonin transporter (Slc6a4/SERT) during early development has paradoxical long-term effects in adult life by increasing vulnerability to depression and anxiety. However, the basis for these developmental effects is not known. Here, we show that during an early postnatal period, (P0-P10), Slc6a4/SERT is transiently expressed in a subset of layer 5-6 pyramidal neurons of the prefrontal cortex (PFC). PFC-SERT+ neurons establish glutamatergic synapses with a number of subcortical targets, including 5-HT and GABA neurons in the dorsal raphe nucleus (DRN). PFC-to-DRN circuits develop postnatally, coinciding with the period of PFC Slc6a4/SERT expression. Complete or cortex-specific ablation of SERT increases the number of functional PFC glutamate synapses onto 5-HT and GABA DRN neurons. This PFC-to-DRN hyper-innervation is replicated by early postnatal exposure to the SSRI fluoxetine from P2to P14, which also causes long-lasting emotional deficits and dampens the activation of the PFC in response to stress. Targeting the PFC-SERT+ neurons with pharmacogenetic tools, we show that chemogenetic inhibition of these neurons enhances the emotional deficits caused by early life exposure to SSRIs. Overall, our data identify specific PFC descending circuits that are targets of antidepressant drugs during the perinatal period. We demonstrate that developmental expression of SERT in a subset of PFC neurons controls synaptic maturation of PFC-to-DRN circuits and that maladaptive changes of these circuits, induced by early exposure to SSRIs, play a central role in behavioral responses to stress.