The serotonin 2B receptor is required in neonatal microglia to limit neuroinflammation and sickness behavior in adulthood

Catherine Béchade (1, 2) , Ivana d'Andrea (1, 2) , Fanny Etienne (1, 2) , Franck Verdonk , Imane Moutkine (1, 2) , Sophie M Banas (1, 2) , Marta Kolodziejczak (1, 2) , Silvina Diaz (1, 2) , Christopher Parkhurst (1) , Wenbiao Gan (3) , Luc Maroteaux (1, 2) , Anne Roumier (1, 2)

1 IFM - Inserm U1270 - SU - Institut du Fer à Moulin
2 Team 5 - Serotonin, Microglia, Plasticity and Pathologies
3 NYU - New York University School of Medicine

Severe peripheral infections induce an adaptive sickness behavior and an innate immune reaction in various organs including the brain. On the long term, persistent alteration of microglia, the brain innate immune cells, is associated with an increased risk of psychiatric disorders. It is thus critical to identify genes and mechanisms controlling the intensity and duration of the neuroinflammation induced by peripheral immune challenges. We tested the hypothesis that the 5-HT2B receptor, the main serotonin receptor expressed by microglia, might represent a valuable candidate. First, we observed that Htr2b-/- mice, knock-out for the 5-HT2B receptor gene, developed, when exposed to a peripheral lipopolysaccharide (LPS) challenge, a stronger weight loss compared to wild-type mice; in addition, comparison of inflammatory markers in brain, 4 and 24 hr after LPS injection, showed that Htr2b deficiency leads to a prolonged neuroinflammation. Second, to assess the specific contribution of the microglial 5-HT2B receptor, we investigated the response to LPS of conditional knock-out mice invalidated for Htr2b in microglia only. We found that deletion of Htr2b in microglia since birth is sufficient to cause enhanced weight loss and increased neuroinflammatory response upon LPS injection at adult stage. In contrast, mice deleted for microglial Htr2b in adulthood responded normally to LPS, revealing a neonatal developmental effect. These results highlight the role of microglia in the response to a peripheral immune challenge and suggest the existence of a developmental, neonatal period, during which instruction of microglia through 5-HT2B receptors is necessary to prevent microglia overreactivity in adulthood.

Mots clés: 5-HT2B receptor; LPS; microglia; neuroinflammation; serotonin; sickness syndrome

Domaines: Psychiatrie et santé mentale; Biologie moléculaire; Génétique animale; Neurobiologie; Pharmacologie

Catherine Béchade, Ivana d'Andrea, Fanny Etienne, Franck Verdonk, Imane Moutkine, et al.. The serotonin 2B receptor is required in neonatal microglia to limit neuroinflammation and sickness behavior in adulthood. Glia, 2020, ⟨10.1002/glia.23918⟩. ⟨hal-02978295⟩