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

Silvina L. Diaz, Nicolas Narboux-Nême, Sara Trowbridge, Sophie Scotto-Lomassese, Felix B. Kleine Borgmann, Sebastian Jessberger, Bruno Giros, Luc Maroteaux, Evan Deneris, Patricia Gaspar*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

35 Citations (Scopus)

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 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. Although increased adult neurogenesis is a neurobiological correlate of the beneficial effects of antidepressants, the consequences of 5-HT depletion are still unclear. We analysed 2 genetic models and a pharmacological model of 5-HT depletion. In all models, including the Pet1-KO mice, we found significant increase in the survival of newborn neurons. Administration of the 5-HT1A receptor agonist 8-OH-DPAT normalised this prosurvival effects. Our results indicate a role of 5-HT in selective neuronal elimination.

Original languageEnglish
Pages (from-to)2650-2658
Number of pages9
JournalEuropean Journal of Neuroscience
Volume38
Issue number5
DOIs
Publication statusPublished - Sep 2013
Externally publishedYes

Keywords

  • 5-hydroxytryptamine depletion
  • Adult neurogenesis
  • Genetic mouse models
  • Hippocampus
  • Para-chlorophenylalanine
  • Pattern separation

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