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

Mol Psychiatry. 2019 May;24(5):726-745. doi: 10.1038/s41380-018-0260-9. Epub 2018 Oct 2.


Antidepressants that block the serotonin transporter, (Slc6a4/SERT), selective serotonin reuptake inhibitors (SSRIs) improve mood in adults but have paradoxical long-term effects when administered during perinatal periods, increasing the risk to develop anxiety and depression. The basis for this developmental effect is not known. Here, we show that during an early postnatal period in mice (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 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 PFC Slc6a4/SERT expression. Complete or cortex-specific ablation of SERT increases the number of functional PFC glutamate synapses on both 5-HT and GABA neurons in the DRN. This PFC-to-DRN hyperinnervation is replicated by early-life exposure to the SSRI, fluoxetine (from P2 to P14), that also causes anxiety/depressive-like symptoms. We show that pharmacogenetic manipulation of PFC-SERT+ neuron activity bidirectionally modulates these symptoms, suggesting that PFC hypofunctionality has a causal role in these altered responses to stress. Overall, our data identify specific PFC descending circuits that are targets of antidepressant drugs during development. We demonstrate that developmental expression of SERT in this subset of PFC neurons controls synaptic maturation of PFC-to-DRN circuits, and that remodeling of these circuits in early life modulates behavioral responses to stress in adulthood.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Anxiety / metabolism
  • Anxiety Disorders / drug therapy
  • Anxiety Disorders / physiopathology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Depression / drug therapy
  • Depression / physiopathology
  • Depressive Disorder / metabolism
  • Disease Models, Animal
  • Dorsal Raphe Nucleus / drug effects
  • Dorsal Raphe Nucleus / metabolism
  • Emotions / drug effects
  • Female
  • GABAergic Neurons / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Pyramidal Cells / metabolism*
  • Selective Serotonin Reuptake Inhibitors / metabolism
  • Selective Serotonin Reuptake Inhibitors / pharmacology*
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / physiology


  • Antidepressive Agents
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Slc6a4 protein, mouse
  • Serotonin