SAN2020

Early-life exposure to antidepressant drugs acting as selective serotonin reuptake inhibitors (SSRIs), like fluoxetine, has long-lasting detrimental consequences in prefrontal circuits crucially engaged in stress-coping and mood control. Thus, mice treated with fluoxetine during a postnatal critical period (P2 to P14) show alterations in the connectivity of the prefrontal cortex to dorsal raphe nucleus (PFC-to-DRN) circuit, accompanied by increases in depressive-like and anxiety behaviors in adult life. In this study, we investigated the short-term effects (at P15) of fluoxetine exposure in the critical period on the synaptic connectivity of the developing PFC-to-DRN circuit, and whether this could affect the response of DRN serotonin neurons to stress. Our quantitative analysis using a high-resolution microscopy technique (array tomography) showed a synaptic hyper-innervation of the developing PFC-to-DRN circuit in fluoxetine-exposed mice in comparison to controls. These changes in PFC afferents were detected onto both serotonin and non-serotonin neurons of the DRN. Additionally, early fluoxetine exposure topographically dampened the activation of DRN serotonin neurons in response to an acute stress (forced swim), as revealed by c-Fos immunohistochemistry. These findings indicate that early-life exposure to SSRIs alters the ontogenetic trajectory of the PFC-to-DRN synaptic circuit, likely contributing to adult emotional alterations.