{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:12:54Z","timestamp":1790835174052,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2015,1,28]],"date-time":"2015-01-28T00:00:00Z","timestamp":1422403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NIH","award":["56NS054278"],"award-info":[{"award-number":["56NS054278"]}]},{"name":"NIH","award":["R01MH084194"],"award-info":[{"award-number":["R01MH084194"]}]},{"name":"NIH","award":["R01NS080844"],"award-info":[{"award-number":["R01NS080844"]}]},{"name":"Department of Pediatrics, University of Mississippi Medical Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2015,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Serotonin (5\u2010hydroxytryptamine, 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content>) has been implicated to play critical roles in early neural development. Recent reports have suggested that perinatal exposure to selective serotonin reuptake inhibitors (<jats:styled-content style=\"fixed-case\">SSRI<\/jats:styled-content>s) resulted in cortical network miswiring, abnormal social behavior, callosal myelin malformation, as well as oligodendrocyte (<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>) pathology in rats. To gain further insight into the cellular and molecular mechanisms underlying<jats:styled-content style=\"fixed-case\">SSRI<\/jats:styled-content>s\u2010induced<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>and myelin abnormalities, we investigated the effect of 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content>exposure on<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>development, cell death, and myelination in cell culture models. First, we showed that 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content>receptor 1A and 2A subtypes were expressed in<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>lineages, using immunocytochemistry, Western blot, as well as intracellular Ca<jats:sup>2+<\/jats:sup>measurement. We then assessed the effect of serotonin exposure on the lineage development, expression of myelin proteins, cell death, and myelination, in purified<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>and neuron\u2010<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>myelination cultures. For pure<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>cultures, our results showed that 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content>exposure led to disturbance of<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>development, as indicated by aberrant process outgrowth and reduced myelin proteins expression. At higher doses, such exposure triggered a development\u2010dependent cell death, as immature<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>s exhibited increasing susceptibility to 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content>treatment compared to<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>progenitor cells (OPC). We showed further that 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content>\u2010induced immature<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>death was\u00a0mediated at least partially via 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content>2A receptor, since cell death could be mimicked by 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content>2A receptor agonist 1\u2010(2,5\u2010dimethoxy\u20104\u2010iodophenyl)\u20102\u2010aminopropane hydrochloride, (\u00b1)\u20102,5\u2010dimethoxy\u20104\u2010iodoamphetamine hydrochloride, but atten\u2010uated by pre\u2010treatment with 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content>2A receptor antagonist ritanserin. Utilizing a neuron\u2010<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>myelination co\u2010culture model, our data showed that 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content>exposure significantly reduced the number of myelinated internodes. In contrast to cell injury observed in pure<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>cultures, 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content>exposure did not lead to<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>death or reduced<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>density in neuron\u2010<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>co\u2010cultures. However, abnormal patterns of contactin\u2010associated protein (Caspr) clustering were observed at the sites of Node of Ranvier, suggesting that 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content>exposure may affect other axon\u2010derived factors for myelination. In summary, this is the first study to demonstrate that manipulation of serotonin levels affects<jats:styled-content style=\"fixed-case\">OL<\/jats:styled-content>development and myelination, which may contribute to altered neural connectivity noted in<jats:styled-content style=\"fixed-case\">SSRI<\/jats:styled-content>s\u2010treated animals.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc12988-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><jats:p>The current<jats:italic>in vitro<\/jats:italic>study demonstrated that exposure to high level of serotonin (5\u2010HT) led to aberrant oligodendrocyte (OL) development, cell injury, and myelination deficit. We propose that elevated extracellular serotonin levels in the fetal brain, such as upon the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy, may adversely affect OL development and\/or myelination, thus contributing to altered neural connectivity seen in Autism Spectrum Disorders. OPC = oligodendrocyte progenitor cell.<\/jats:p>","DOI":"10.1111\/jnc.12988","type":"journal-article","created":{"date-parts":[[2014,11,10]],"date-time":"2014-11-10T12:03:56Z","timestamp":1415621036000},"page":"532-543","source":"Crossref","is-referenced-by-count":71,"title":["Exposure to serotonin adversely affects oligodendrocyte development and myelination<i>in vitro<\/i>"],"prefix":"10.1111","volume":"133","author":[{"given":"Lir\u2010Wan","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Pediatrics University of Mississippi Medical Center Jackson Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhay","family":"Bhatt","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of Mississippi Medical Center Jackson Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu\u2010Tai","family":"Tien","sequence":"additional","affiliation":[{"name":"School of Medicine Fu Jen Catholic University Xinzhuang Dist New Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoying","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Mississippi Medical Center Jackson Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly L.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Neurobiology and Anatomical Sciences University of Mississippi Medical Center Jackson Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick C. 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