Alterations in CA1 hippocampal synapses in a mouse model of fragile X syndrome

Jawaid Safdar; Kidd Grahame J.; Wang Jing; Swetlik Carrie; Dutta Ranjan; Trapp Bruce D.

摘要

Abstract > Fragile X Syndrome (FXS) is the major cause of inherited mental retardation and the leading genetic cause of Autism spectrum disorders. FXS is caused by mutations in the Fragile X Mental Retardation 1 (Fmr1) gene, which results in transcriptional silencing of Fragile X Mental Retardation Protein (FMRP). To elucidate cellular mechanisms involved in the pathogenesis of FXS, we compared dendritic spines in the hippocampal CA1 region of adult wild‐type (WT) and Fmr1 knockout (Fmr1‐KO) mice. Using diolistic labeling, confocal microscopy, and three‐dimensional electron microscopy, we show a significant increase in the diameter of secondary dendrites, an increase in dendritic spine density, and a decrease in mature dendritic spines in adult Fmr1‐KO mice. While WT and Fmr1‐KO mice had the same mean density of spines, the variance in spine density was three times greater in Fmr1‐KO mice. Reduced astrocyte participation in the tripartite synapse and less mature post‐synaptic densities were also found in Fmr1‐KO mice. We investigated whether the increase in synaptic spine density was associated with altered synaptic pruning during development. Our data are consistent with reduced microglia‐mediated synaptic pruning in the CA1 region of Fmr1‐KO hippocampi when compared with WT littermates at postnatal day 21, which is the peak period of synaptic pruning in the mouse hippocampus. Collectively, these results support abnormal synaptogenesis and synaptic remodeling in mice deficient in FMRP. Deficits in the maturation and distribution of synaptic spines on dendrites of CA1 hippocampal neurons may play a role in the intellectual disabilities associated with FXS. </abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> <div class="translation abstracttxt"> <span class="zhankaihshouqi fivelineshidden" id="abstract"> <span>机译：</span><Abstract XMLNS =“http://www.wiley.com/namespaces/wiley”type =“main”> <title type =“main”>抽象</ title> >易碎x综合征（fxs）是主要的继承精神迟滞的原因与自闭症谱系障碍的主要遗传原因。 FXS是由脆弱的X精神迟滞1（FMR1）基因中的突变引起的，这导致脆弱X精神迟发蛋白（FMRP）的转录沉默。为了阐明参与FXS发病机制的细胞机制，我们将树突刺与成人野生型（WT）和 FMR1敲除（FMR1-KO）小鼠的敲除（FMR1-KO）小鼠的敲除（FMR1-KO）小鼠进行了比较。使用DioListic标记，共聚焦显微镜和三维电子显微镜，我们显着增加了次级树枝状的直径，树枝状脊柱密度的增加，成熟FMR1-KO小鼠的成熟树突刺降低。虽然WT和FMR1-KO小鼠具有相同的血管密度，但在FMR1-KO小鼠中，脊柱密度的方差是较高的三倍。在FMR1-KO小鼠中也发现了减少的星形胶质细胞参与三方突触和较少的突触后密度。我们调查了突触脊柱密度的增加是否与开发过程中改变的突触修剪相关。当与产后第21天的WT凋落物相比，我们的数据与FMR1-KO海马的CA1区域中的CA1区域中的细微介导的突触序列一致。总的来说，这些结果支持FMRP缺乏小鼠的异常突触和突触重塑。 Ca1海马神经元树突上突触刺的成熟和分布的缺陷可能在与FXS相关的智力中发挥作用。 </ p> </ abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> </div> <div class="record"> <h2 class="all_title" id="enpatent33" >著录项</h2> <ul> <li> <span class="lefttit">来源</span> <div style="width: 86%;vertical-align: text-top;display: inline-block;"> <a href='/journal-foreign-23771/'>《Glia》</a> <b style="margin: 0 2px;">|</b><span>2018年第4期</span><b style="margin: 0 2px;">|</b><span>共12页</span> </div> </li> <li> <div class="author"> <span class="lefttit">作者</span> <p id="fAuthorthree" class="threelineshidden zhankaihshouqi"> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Jawaid Safdar&option=202" target="_blank" rel="nofollow">Jawaid Safdar;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Kidd Grahame J.&option=202" target="_blank" rel="nofollow">Kidd Grahame J.;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Wang Jing&option=202" target="_blank" rel="nofollow">Wang Jing;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Swetlik Carrie&option=202" target="_blank" rel="nofollow">Swetlik Carrie;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Dutta Ranjan&option=202" target="_blank" rel="nofollow">Dutta Ranjan;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Trapp Bruce D.&option=202" target="_blank" rel="nofollow">Trapp Bruce D.;</a> </p> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zkzz" style="display: none;">展开▼</span> </div> </li> <li> <div style="display: flex;"> <span class="lefttit">作者单位</span> <div style="position: relative;margin-left: 3px;max-width: 639px;"> <div class="threelineshidden zhankaihshouqi" id="fOrgthree"> <p>Department of NeurosciencesLerner Research Institute Cleveland ClinicCleveland Ohio;</p> <p>Department of NeurosciencesLerner Research Institute Cleveland ClinicCleveland Ohio;</p> <p>Department of NeurosciencesLerner Research Institute Cleveland ClinicCleveland Ohio;</p> <p>Department of NeurosciencesLerner Research Institute Cleveland ClinicCleveland Ohio;</p> <p>Department of NeurosciencesLerner Research Institute Cleveland ClinicCleveland Ohio;</p> <p>Department of NeurosciencesLerner Research Institute Cleveland ClinicCleveland Ohio;</p> </div> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zhdw" style="display: none;">展开▼</span> </div> </div> </li> <li > <span class="lefttit">收录信息</span> <span style="width: 86%;vertical-align: text-top;display: inline-block;"></span> </li> <li> <span class="lefttit">原文格式</span> <span>PDF</span> </li> <li> <span class="lefttit">正文语种</span> <span>eng</span> </li> <li> <span class="lefttit">中图分类</span> <span><a href="https://www.zhangqiaokeyan.com/clc/200.html" title="神经病学与精神病学">神经病学与精神病学;</a></span> </li> <li class="antistop"> <span class="lefttit">关键词</span> <p style="width: 86%;vertical-align: text-top;"> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=astrocyte&option=203" rel="nofollow">astrocyte;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=microglia&option=203" rel="nofollow">microglia;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=post‐synaptic density&option=203" rel="nofollow">post‐synaptic density;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=tripartite synapse&option=203" rel="nofollow">tripartite synapse;</a> </p> <div class="translation"> 机译：星形胶质细胞;小胶质细胞;突触后密度;三方突触; 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