title: Paradoxical increase in survival of newborn neurons in the dentate gyrus of mice with constitutive depletion of serotonin.
abstract: Increased adult neurogenesis is a major neurobiological correlate of the beneficial effects of antidepressants. Indeed, selective serotonin (5-HT) re-uptake inhibitors, which increase 5-HT transmission, enhance adult neurogenesis in the dentate gyrus (DG) of the hippocampus. However, the consequences of 5-HT depletion are still unclear as studies using neurotoxins that target serotonergic neurons reached contradictory conclusions on the role of 5-HT on DG cell proliferation. Here, we analysed two genetic models of 5-HT depletion, the Pet1(-/-) and the VMAT2(f/f) ; SERT(cre/+) mice, which have, respectively, 80 and 95% reductions in hippocampal 5-HT. In both models, we found unchanged cell proliferation of the neural precursors in the DG subgranular zone, whereas a significant increase in the survival of newborn neurons was noted 1 and 4 weeks after BrdU injections. This pro-survival trait was phenocopied pharmacologically with 5-HT synthesis inhibitor PCPA treatment in adults, indicating that this effect was not developmental. Furthermore, a 1-week administration of the 5-HT1A receptor agonist 8-OH-DPAT in Pet1(-/-) and PCPA-treated mice normalised hippocampal cell survival. Overall, our results indicate that constitutive 5-HT depletion does not alter the proliferation of neural precursors in the DG but promotes the survival of newborn cells, an effect which involves activation of postsynaptic 5-HT1A receptors. The role of 5-HT in selective neuronal elimination points to a new facet in its multiple effects in controlling neural circuit maturation.
authors.affiliation: Inserm, UMR-S 839, France.
authors.forename: Silvina L
authors.initials: SL
authors.lastname: Diaz
authors.forename: Nicolas
authors.initials: N
authors.lastname: Narboux-Nême
authors.forename: Sara
authors.initials: S
authors.lastname: Trowbridge
authors.forename: Sophie
authors.initials: S
authors.lastname: Scotto-Lomassese
authors.forename: Felix B
authors.initials: FB
authors.lastname: Kleine Borgmann
authors.forename: Sebastian
authors.initials: S
authors.lastname: Jessberger
authors.forename: Bruno
authors.initials: B
authors.lastname: Giros
authors.forename: Luc
authors.initials: L
authors.lastname: Maroteaux
authors.forename: Evan
authors.initials: E
authors.lastname: Deneris
authors.forename: Patricia
authors.initials: P
authors.lastname: Gaspar
mesh_terms: D000818:Animals; D002470:Cell Survival; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism*; D005260:Female; D010134:Fenclonine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology*; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics
chemical_list: D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D012701:Serotonin; D010134:Fenclonine
keywords: 5-hydroxytryptamine depletion; adult neurogenesis; genetic mouse models; hippocampus; para-chlorophenylalanine; pattern separation