SSRIs target prefrontal to raphe circuits during development modulating synaptic connectivity and emotional behavior.
Animals
Antidepressive Agents
/ pharmacology
Anxiety
/ metabolism
Anxiety Disorders
/ drug therapy
Cerebral Cortex
/ drug effects
Depression
/ drug therapy
Depressive Disorder
/ metabolism
Disease Models, Animal
Dorsal Raphe Nucleus
/ drug effects
Emotions
/ drug effects
Female
GABAergic Neurons
/ metabolism
Male
Mice
Mice, Inbred C57BL
Prefrontal Cortex
/ drug effects
Pyramidal Cells
/ metabolism
Serotonin
/ metabolism
Serotonin Plasma Membrane Transport Proteins
/ metabolism
Selective Serotonin Reuptake Inhibitors
/ metabolism
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
14
03
2018
accepted:
06
09
2018
revised:
08
08
2018
pubmed:
4
10
2018
medline:
4
3
2020
entrez:
4
10
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30279456
doi: 10.1038/s41380-018-0260-9
pii: 10.1038/s41380-018-0260-9
pmc: PMC6445781
mid: NIHMS1506070
doi:
Substances chimiques
Antidepressive Agents
0
Serotonin Plasma Membrane Transport Proteins
0
Serotonin Uptake Inhibitors
0
Slc6a4 protein, mouse
0
Serotonin
333DO1RDJY
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
726-745Subventions
Organisme : NIMH NIH HHS
ID : R01 MH105839
Pays : United States
Organisme : NIMH NIH HHS
ID : R21 MH098290
Pays : United States
Organisme : NIMH NIH HHS
ID : R56 MH105839
Pays : United States
Commentaires et corrections
Type : ErratumIn
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