The proper maturation of emotional and sensory circuits requires fine-tuning of serotonin (5-HT) level during early postnatal development. Consistently, dysfunctions of the serotonergic system have been associated with neurodevelopmental psychiatric diseases, including autism spectrum disorders (ASD). However, the mechanisms underlying the developmental effects of 5-HT remain partially unknown, one obstacle being the action of 5-HT on different cell types. Here, we focused on microglia, which play a role in brain wiring refinement, and we investigated whether the control of these cells by 5-HT is relevant for neurodevelopment and spontaneous behaviors in mice. Since the main 5-HT sensor in microglia is the 5-HT2B receptor subtype, we prevented 5-HT signaling specifically in microglia by conditional invalidation of the Htr2b gene in these cells. We observed that abrogating the serotonergic control of microglia during early postnatal development affects the phagolysosomal compartment of these cells and their proximity to dendritic spines and perturbs neuronal circuits maturation. Furthermore, this early ablation of microglial 5-HT2B receptors leads to adult hyperactivity in a novel environment and behavioral defects in sociability and flexibility. Importantly, we show that these behavioral alterations result from a developmental effect, since they are not observed when microglial Htr2b invalidation is induced later, at P30 onward. Thus, a primary alteration of 5-HT sensing in microglia, during a critical time window between birth and P30, is sufficient to impair social and flexibility skills. This link between 5-HT and microglia may explain the association between serotonergic dysfunctions and behavioral traits like impaired sociability and inadaptability to novelty, which are prominent in psychiatric disorders such as ASD.
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We thank Chris N. Parkhurst and Wenbiao B. Gan for providing the Cx3cr1creERT2 knock-in mice, the Cell and Tissue Imaging Facility of the Institut du Fer à Moulin (namely Theano Eirinopoulou, Mythili Savariradjane, and Xavier Marquès), where all image acquisitions and analyses have been performed, and the staff of the IFM animal facility (namely Baptiste Lecomte, Gaël Grannec, François Baudon, Anna-Sophia Mourenco, Emma Courteau and Eloise Marsan). We warmly thank Patricia Gaspar, Ludmilla Lokmane, Sonia Garel, Véronique Fabre and Jean Christophe Poncer for the discussion and revision. This work has been supported by grants from the Agence Nationale de la Recherche (ANR-17-CE16-0008, ANR-11-IDEX-0004-02), the Fondation pour la Recherche Médicale (Equipe FRM DEQ2014039529) and the Fédération pour la Recherche sur le Cerveau (FRC-2019-19F10).
The authors declare no competing interests.
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Albertini, G., D’Andrea, I., Druart, M. et al. Serotonin sensing by microglia conditions the proper development of neuronal circuits and of social and adaptive skills. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02048-5