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

M. Soiza-Reilly, F. J. Meye, J. Olusakin, L. Telley, E. Petit, X. Chen, M. Mameli, D. Jabaudon, Ji Ying Sze, P. Gaspar

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)726-745
Number of pages20
JournalMolecular Psychiatry
Volume24
Issue number5
DOIs
StatePublished - May 1 2019

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Serotonin Uptake Inhibitors
Prefrontal Cortex
GABAergic Neurons
Serotonin
Neurons
Synapses
Antidepressive Agents
Anxiety
Depression
Serotonin Plasma Membrane Transport Proteins
Pyramidal Cells
Fluoxetine
Pharmacogenetics
Glutamic Acid
Dorsal Raphe Nucleus

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Soiza-Reilly, M., Meye, F. J., Olusakin, J., Telley, L., Petit, E., Chen, X., ... Gaspar, P. (2019). SSRIs target prefrontal to raphe circuits during development modulating synaptic connectivity and emotional behavior. Molecular Psychiatry, 24(5), 726-745. https://doi.org/10.1038/s41380-018-0260-9

SSRIs target prefrontal to raphe circuits during development modulating synaptic connectivity and emotional behavior. / Soiza-Reilly, M.; Meye, F. J.; Olusakin, J.; Telley, L.; Petit, E.; Chen, X.; Mameli, M.; Jabaudon, D.; Sze, Ji Ying; Gaspar, P.

In: Molecular Psychiatry, Vol. 24, No. 5, 01.05.2019, p. 726-745.

Research output: Contribution to journalArticle

Soiza-Reilly, M, Meye, FJ, Olusakin, J, Telley, L, Petit, E, Chen, X, Mameli, M, Jabaudon, D, Sze, JY & Gaspar, P 2019, 'SSRIs target prefrontal to raphe circuits during development modulating synaptic connectivity and emotional behavior', Molecular Psychiatry, vol. 24, no. 5, pp. 726-745. https://doi.org/10.1038/s41380-018-0260-9
Soiza-Reilly, M. ; Meye, F. J. ; Olusakin, J. ; Telley, L. ; Petit, E. ; Chen, X. ; Mameli, M. ; Jabaudon, D. ; Sze, Ji Ying ; Gaspar, P. / SSRIs target prefrontal to raphe circuits during development modulating synaptic connectivity and emotional behavior. In: Molecular Psychiatry. 2019 ; Vol. 24, No. 5. pp. 726-745.
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AU - Meye, F. J.

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AU - Petit, E.

AU - Chen, X.

AU - Mameli, M.

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AU - Sze, Ji Ying

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