Serotonin sensing by microglia conditions the proper development of neuronal circuits and of social and adaptive skills

5-羟色胺能 小胶质细胞 神经科学 生物神经网络 血清素 5-羟色胺受体 自闭症 心理学 受体 生物 医学 炎症 发展心理学 免疫学 内科学
作者
Giulia Albertini,Ivana D’Andrea,Mélanie Druart,Catherine Béchade,Nayadoleni Nieves-Rivera,Fanny Etienne,Corentin Le Magueresse,Alexandra Rebsam,Nicolas Heck,Luc Maroteaux,Anne Roumier
标识
DOI:10.1101/2022.03.09.483609
摘要

Abstract The proper maturation of emotional and sensory circuits requires a 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. Since the main 5-HT sensor in microglia is the 5-HT 2B receptor subtype, we prevented 5-HT signaling specifically in microglia by conditionally invalidating Htr2b gene in these cells. We observed that abrogating the serotonergic control of microglia neonatally impacts the phagolysosomal compartment of these cells and their proximity to synapses, and perturbs neuronal circuits maturation. Furthermore, this early ablation of microglial 5-HT 2B 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 several psychiatric disorders such as ASD.
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