Idiopathic Autism: Cellular and Molecular Phenotypes in Pluripotent Stem Cell-Derived Neurons.
Idiopathic Autism: Cellular and Molecular Phenotypes in Pluripotent Stem Cell-Derived Neurons.
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DOI：
10.1007/s12035-016-9961-8
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发表时间：
2017-08
影响因子：
5.1
通讯作者：
Rennert, Owen M.
中科院分区：
文献类型：
--
作者：
Liu, Xiaozhuo;Campanac, Emilie;Cheung, Hoi-Hung;Ziats, Mark N.;Canterel-Thouennon, Lucile;Raygada, Margarita;Baxendale, Vanessa;Pang, Alan Lap-Yin;Yang, Lu;Swedo, Susan;Thurm, Audrey;Lee, Tin-Lap;Fung, Kwok-Pui;Chan, Wai-Yee;Hoffman, Dax A.;Rennert, Owen M.
关键词：
自闭症谱系障碍是一种复杂的神经发育障碍，由于缺乏对患者大脑神经元的研究，其病理生理学仍然难以捉摸；这种缺陷可能被诱导多能干细胞的神经分化所规避。具有单基因突变和自闭症症状的罕见综合征显著推进了对自闭症谱系障碍的分子和细胞理解，然而，总的来说，它们只代表了自闭症所有病例的一小部分。为了确定非综合征型自闭症人类神经元的细胞和分子表型，我们从三名没有可识别临床综合征的男性自闭症谱系障碍患者及其未受影响的男性兄弟姐妹中提取了诱导多能干细胞（iPSCs），并随后将这些患者特异性干细胞分化为电生理活跃的神经元。与对照组相比，来自这些自闭症患者的ipsc衍生神经元显示出自发兴奋性突触后电流的频率和动力学降低，以及Na+和K+灭活电压门控电流的显著降低。此外，基因表达的全基因组微阵列分析鉴定出161个独特基因在自闭症患者ipscs来源的神经元中显著差异表达（>两倍，FDR < 0.05）。这些基因在突触传递相关过程中显著富集，如神经活性配体-受体信号传导和细胞外基质相互作用，并且在先前与自闭症谱系障碍相关的基因中富集。我们的数据表明，与未受影响的兄弟姐妹对照相比，特发性自闭症患者的ipscs衍生神经元中存在异常的电压门控电流和与突触功能相关的潜在分子变化。
Autism spectrum disorder is a complex neurodevelopmental disorder whose pathophysiology remains elusive as a consequence of the unavailability for study of patient brain neurons; this deficit may potentially be circumvented by neural differentiation of induced pluripotent stem cells. Rare syndromes with single gene mutations and autistic symptoms have significantly advanced the molecular and cellular understanding of autism spectrum disorders, however, in aggregate they only represent a fraction of all cases of autism. In an effort to define the cellular and molecular phenotypes in human neurons of non-syndromic autism we generated induced pluripotent stem cells (iPSCs) from three male autism spectrum disorder patients who had no identifiable clinical syndromes, and their unaffected male siblings and subsequently differentiated these patient-specific stem cells into electrophysiologically active neurons. iPSC-derived neurons from these autistic patients displayed decreases in the frequency and kinetics of spontaneous excitatory postsynaptic currents relative to controls, as well as significant decreases in Na+ and inactivating K+ voltage-gated currents. Moreover, whole-genome microarray analysis of gene expression identified 161 unique genes that were significantly differentially expressed in autistic patients iPSCs-derived neurons (> two-fold, FDR < 0·05). These genes were significantly enriched for processes related to synaptic transmission, such as neuroactive ligand-receptor signaling and extracellular matrix interactions, and were enriched for genes previously associated with autism spectrum disorder. Our data demonstrate aberrant voltage-gated currents and underlying molecular changes related to synaptic function in iPSCs-derived neurons from individuals with idiopathic autism as compared to unaffected siblings controls.
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影响因子：
12.3
作者：
Carroll LS;Owen MJ
通讯作者：
Owen MJ
DOI：
10.1016/j.jaac.2013.12.021
发表时间：
2014-05-01
影响因子：
13.3
作者：
Kim, Young Shin;Fombonne, Eric;Leventhal, Bennett L.
通讯作者：
Leventhal, Bennett L.
影响因子：
3.9
作者：
Lord, C;Risi, S;Rutter, M
通讯作者：
Rutter, M
对非综合自闭症进行建模以及TRPC6破坏在人神经元中的影响。
影响因子：
11
作者：
Griesi-Oliveira, K.;Acab, A.;Gupta, A. R.;Sunaga, D. Y.;Chailangkarn, T.;Nicol, X.;Nunez, Y.;Walker, M. F.;Murdoch, J. D.;Sanders, S. J.;Fernandez, T. V.;Ji, W.;Lifton, R. P.;Vadasz, E.;Dietrich, A.;Pradhan, D.;Song, H.;Ming, G-I;Gu, X.;Haddad, G.;Marchetto, M. C. N.;Spitzer, N.;Passos-Bueno, M. R.;State, M. W.;Muotri, A. R.
通讯作者：
Muotri, A. R.
影响因子：
64.5
作者：
Michaelson JJ;Shi Y;Gujral M;Zheng H;Malhotra D;Jin X;Jian M;Liu G;Greer D;Bhandari A;Wu W;Corominas R;Peoples A;Koren A;Gore A;Kang S;Lin GN;Estabillo J;Gadomski T;Singh B;Zhang K;Akshoomoff N;Corsello C;McCarroll S;Iakoucheva LM;Li Y;Wang J;Sebat J
通讯作者：
Sebat J