Exposure to serotonin adversely affects oligodendrocyte development and myelination in vitro

Abstract

Serotonin (5-hydroxytraptamin, 5-HT) has been implicated to play critical roles in early neural development. Recent reports have suggested that perinatal exposure to selective serotonin reuptake inhibitors (SSRIs) resulted in cortical network miswiring, abnormal social behavior, callosal myelin malformation, as well as oligodendrocytes (OL) pathology in rats. To gain further insight into the cellular and molecular mechanisms underlying SSRIs-induced OL and myelin abnormalities, we investigated the effect of 5-HT exposure on OL development, cell death, and myelination in cell culture models. First, we showed that 5-HT receptor 1A and 2A subtypes were expressed in OL lineages, using immunocytochemistry, Western blot, as well as intracellular Ca2+ measurement. We then assessed the effect of serotonin exposure on the lineage development, expression of myelin proteins, cell death, and myelination, in purified OL and neuron-OL myelination cultures. For pure OL cultures, our results showed that 5-HT exposure led to disturbance of OL development, as indicated by aberrant process outgrowth and reduced myelin proteins expression. At higher doses, such exposure triggered a development-dependent cell death, as immature OLs exhibited increasing susceptibility to 5-HT treatment compared to OL progenitor cells (OPCs). We showed further that 5-HT-induced immature OL death was mediated at least partially via 5-HT2A receptor, since cell death could be mimicked by 5-HT2A receptor agonist DOI, but attenuated by pre-treatment with 5-HT2A receptor antagonist ritanserin. Utilizing a neuron-OL myelination co-culture model, our data showed that 5-HT exposure significantly reduced the number of myelinated internodes. In contrast to cell injury observed in pure OL cultures, 5-HT exposure did not lead to OL death or reduced OL density in neuron-OL co-cultures. However, abnormal patterns of contactin-associated protein (Caspr) clustering were observed at the sites of Node of Ranvier, suggesting that 5-HT exposure may affect other axon-derived factors for myelination. In summary, this is the first study to demonstrate that manipulation of serotonin levels affects OL development and myelination, which may contribute to altered neural connectivity noted in SSRIs-treated animals.

Antenatal depression, treatment with selective serotonin reuptake inhibitors, and neonatal brain structure: A propensity-matched cohort study

“…This is not entirely surprising as the serotonin transporter (5HTT) is expressed broadly during development (Narboux-Neme et al, 2008). Furthermore, in vitro studies suggest that elevated extracellular 5-HT levels adversely affect the survival and development of oligodendrocytes (Fan et al, 2015) while early life exposure to SSRIs produces ultrastructural abnormalities of white matter oligodendrocytes and myelin sheaths in corpus callosum (Simpson et al, 2011) and downregulation of myelination-related genes in the hippocampus of adult rats,(Kroeze et al, 2015), suggesting SSRIs alter key myelination processes in diverse brain regions.…”

Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: The forgotten partner

“…5-hydroxytryptamine (5-HT) receptor subtypes 1 A and 2 A are expressed in immature and myelinating oligodendrocytes (Fan et al, 2015). Its activation after exposure to serotonin interferes with oligodendroglial differentiation and myelinogenesis (Persico et al, 2000;Fan et al, 2015).…”

Electrophysiological properties of NG2 + cells: Matching physiological studies with gene expression profiles

“…A recent study used immunohistochemistry and Western blot to assess 5-HT 1A and 5-HT 2A receptor expression in cultured rat oligodendrocyte lineage cells, and expression of both receptors was found throughout the lineage (Fan et al, 2015). Intracellular Ca 2+ elevation was also detected in response to serotonin, and chronic serotonin or 5-HT 2A receptor agonist administration reduced differentiation of pure cultured NG2 + cells and reduced myelination of axons in co-cultures.…”