Serotonin Modulates Developmental Microglia via 5-HT_2B Receptors: Potential Implication during Synaptic Refinement of Retinogeniculate Projections

Abstract

Abstract.Maturation of functional neuronal circuits during central nervous system development relies on sophisticated mechanisms. First, axonal and dendritic growth should reach appropriate targets for correct synapse elaboration. Second, pruning and neuronal death are required to eliminate redundant or inappropriate neuronal connections. Serotonin, in addition to its role as a neurotransmitter, actively participates in postnatal establishment and refinement of brain wiring in mammals. Brain resident macrophages, i.e. microglia, also play an important role in developmentally-regulated neuronal death as well as in synaptic maturation and elimination. Here, we tested the hypothesis of cross-regulation between microglia and serotonin during postnatal brain development in a mouse model of synaptic refinement. We found expression of the serotonin 5-HT 2B receptor on postnatal microglia, suggesting that serotonin could participate in temporal and spatial synchronization of microglial functions. Using two-photon microscopy, acute brain slices and local delivery of serotonin, we observed that microglial processes moved rapidly toward the source of serotonin in Htr 2B +/+ mice, but not in Htr 2B-/-mice lacking the 5-HT 2B receptor. We then investigated whether some developmental steps known to be controlled by serotonin, could potentially result from microglia sensitivity to serotonin. Using an in vivo model of synaptic refinement during early brain development, we investigated the maturation of the retinal projections to the thalamus and observed that Htr 2B -/-mice present anatomical alterations of the ipsilateral projecting area of retinal axons into the thalamus. In addition, activation markers were upregulated in microglia from Htr 2B -/-compared to control neonates, in the absence of apparent morphological modifications. These results support the hypothesis that serotonin interacts with microglial cells and these interactions participate in brain maturation.

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

“…Thus, the current knowledge of the function of Htr2b in microglial cells remains limited to in vitro studies (this study (Fig. 7) or previous results [40]). The generation and characterization of knock-out mice in which Htr2b deletion is restricted to microglia will yield invaluable insights into this question.…”

“…In human peripheral macrophages, 5-HT 2B R mediates the response to serotonin by skewing macrophages to a M2, anti-inflammatory, phenotype [14]. More relevant to ALS, we showed that 5-HT 2B R is the major serotonin receptor expressed on perinatal microglia and regulates chemotaxis of microglial processes in response to serotonin [40]. These findings raise the possibility that the observed 5-HT 2B R upregulation could be linked to microglial activation and function in the pathogenesis of ALS.…”

“…The hypothesis that degeneration of mononuclear phagocytes is directly linked to the lack of 5-HT 2B R in this cell type is plausible for several reasons. First, Htr2b expression has been detected in newborn brain microglia [40] although it remains low in basal conditions [12,8,7,31]. Htr2b is also highly expressed in peripheral macrophages [14].…”

“…Since 5-HT 2B R is expressed in microglia and peripheral macrophages [14,40], increased 5-HT 2B R expression could reflect microglial activation and/or infiltrated monocyte activation. To address this question, we purified CD11b positive cells from late stage SOD1(G86R) mice using magnetic bead cell sorting, followed by RT-qPCR.…”

“…5-HT 2B R is expressed in microglia in the CNS [40], with expression in other cell types including brain serotonin neurons [16]. In human peripheral macrophages, 5-HT 2B R mediates the response to serotonin by skewing macrophages to a M2, anti-inflammatory, phenotype [14].…”