Exposure to serotonin adversely affects oligodendrocyte development and myelination in vitro.
Exposure to serotonin adversely affects oligodendrocyte development and myelination in vitro.
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DOI：
10.1111/jnc.12988
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发表时间：
2015-05
影响因子：
4.7
通讯作者：
Pang Y
中科院分区：
文献类型：
--
作者：
Fan LW;Bhatt A;Tien LT;Zheng B;Simpson KL;Lin RC;Cai Z;Kumar P;Pang Y
5-羟色胺（5-hydroxytraptamin，5-HT）在早期神经发育中起重要作用。最近的报告表明，围产期暴露于选择性5-羟色胺再摄取抑制剂（SSRIs）导致皮质网络布线错误，异常的社会行为，胼胝体髓鞘畸形，以及少突胶质细胞（OL）的病理。为了进一步了解SSRIs诱导的OL和髓鞘异常的细胞和分子机制，我们研究了5-HT暴露对OL发育、细胞死亡和细胞培养模型中髓鞘形成的影响。首先，我们发现，5-HT受体1A和2A亚型在OL谱系中表达，使用免疫细胞化学，Western印迹，以及细胞内Ca 2+测量。然后，我们评估了5-羟色胺暴露对纯化的OL和神经元-OL髓鞘形成培养物中的谱系发育、髓鞘蛋白表达、细胞死亡和髓鞘形成的影响。对于纯OL文化，我们的研究结果表明，5-HT暴露导致OL发展的障碍，异常的过程生长和髓鞘蛋白表达减少。在较高剂量下，这种暴露引发了发育依赖性细胞死亡，因为与OL祖细胞（OPC）相比，未成熟OL表现出对5-HT处理的敏感性增加。我们进一步表明，5-HT诱导的未成熟OL死亡至少部分是通过5-HT 2A受体介导的，因为细胞死亡可以被5-HT 2A受体激动剂DOI模拟，但被5-HT 2A受体拮抗剂ritanserin预处理减弱。利用神经元-OL髓鞘形成共培养模型，我们的数据表明，5-HT暴露显着减少有髓鞘的节间的数量。与纯OL培养物中观察到的细胞损伤相反，5-HT暴露不会导致OL死亡或神经元-OL共培养物中OL密度降低。然而，接触素相关蛋白（Caspr）聚类的异常模式，观察到在节点的Ranvier，这表明5-HT暴露可能会影响其他轴突衍生的髓鞘形成的因素。总之，这是第一项证明操纵5-羟色胺水平影响OL发育和髓鞘形成的研究，这可能有助于改变SSRIs治疗动物中观察到的神经连接。
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.
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影响因子：
3.3
作者：
Bonnin, A.;Peng, W.;Levitt, P.
通讯作者：
Levitt, P.
DOI：
10.1073/pnas.0501509102
发表时间：
2005-04-12
影响因子：
11.1
作者：
Esaki, T;Cook, M;Holmes, A
通讯作者：
Holmes, A
影响因子：
3.7
作者：
Persico, AM;Altamura, C;Keller, F
通讯作者：
Keller, F
影响因子：
5.4
作者：
Schaumburg, C.;O'Hara, B. A.;Atwood, W. J.
通讯作者：
Atwood, W. J.
影响因子：
--
作者：
Levitt, Pat
通讯作者：
Levitt, Pat