Paradoxical increase in survival of newborn neurons in the dentate gyrus of mice with constitutive depletion of serotonin

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 VMAT2f/f; SERTcre/+ 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.Fil: Diaz, Silvina Laura. Inserm; Francia. Universite Pierre et Marie Curie; Francia. Institut du Fer à Moulin; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencias "Profesor Eduardo de Robertis"; ArgentinaFil: Narboux Nême, Nicolas. Inserm; Francia. Universite Pierre et Marie Curie; Francia. Institut du Fer à Moulin; FranciaFil: Trowbridge, Sara. Inserm; Francia. Universite Pierre et Marie Curie; Francia. Institut du Fer à Moulin; FranciaFil: Scotto Lomassese, Sophie. Inserm; Francia. Universite Pierre et Marie Curie; Francia. Institut du Fer à Moulin; FranciaFil: Kleine Borgemann, Felix B.. Universitat Zurich; SuizaFil: Jessberger, Sebastian. Universitat Zurich; SuizaFil: Giros, Bruno. Universite Pierre Et Marie Curie; Francia. Centre National de la Recherche Scientifique; Francia. Mc Gill University; CanadáFil: Maroteaux, Luc. Inserm; Francia. Universite Pierre et Marie Curie; Francia. Institut du Fer à Moulin; FranciaFil: Deneris, Evan. Case Western Reserve University; Estados UnidosFil: Gaspar, Patricia. Inserm; Francia. Universite Pierre et Marie Curie; Francia. Institut du Fer à Moulin; Franci