Cortical serotonin transporter cell-autonomously controls synaptic wiring of subcortical prefrontal circuits

SOIZA REILLY M

Bordeaux

Conferencia; 15th Meeting of the Development of Neural Networks Club; 2017

Development of Neural Networks Club

Antidepressants thatinhibit the serotonin transporter (Slc6a4/SERT) have paradoxical effects duringdevelopment on adult mood, the basis of which is not known. Here, we reportthat during an early postnatal period (P0-P10), Slc6a4/SERT is transientlyexpressed in a subset of layers 5-6 pyramidal cortical neurons of the mouseprefrontal cortex (PFC). PFC-SERT+ neurons establish glutamatergic synapseswith a number of subcortical targets including the mediodorsal thalamus anddorsal raphe nucleus (DRN). Transcriptome profiling indicates that Slc6a4/SERTexpression in PFC neurons controls the expression of genes involved in axongrowth and synaptic maturation and function. Accordingly, complete orcortex-specific ablation of Slc6a4/SERT causes hyper-innervation of descendingsynaptic circuits such as the PFC-to-DRN circuit, in in which PFC-SERT+ neuronsare largely engaged. Furthermore, pharmacological blockade of Slc6a4/SERT withthe antidepressant fluoxetine during a mood-related developmental criticalperiod (P2-P14) is sufficient to reproduce these effects. Consistently,Slc6a4/SERT invalidation results in increased number of functional glutamatesynapses within the PFC-to-DRN circuit on both 5-HT and GABA neurons in theDRN. Overall our data identify specific PFC descending circuits that are targetof antidepressant drugs during the perinatal period. We demonstrate thatSlc6a4/SERT in these cortical neurons controls the synaptic maturation of thePFC-to-DRN circuit that is known to play a central role in stress and moodcontrol.