Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndrome.
Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndrome.
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DOI：
10.1176/appi.ajp.2010.10040484
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发表时间：
2010-12
期刊：
影响因子：
--
通讯作者：
Holmes A
中科院分区：
文献类型：
--
作者：
Feyder M;Karlsson RM;Mathur P;Lyman M;Bock R;Momenan R;Munasinghe J;Scattoni ML;Ihne J;Camp M;Graybeal C;Strathdee D;Begg A;Alvarez VA;Kirsch P;Rietschel M;Cichon S;Walter H;Meyer-Lindenberg A;Grant SG;Holmes A
越来越多的研究将自闭症谱系障碍和其他神经发育障碍与突触异常（“突触病变”）联系起来。PSD-95（突触后密度-95，DLG4）在兴奋性突触中协调蛋白-蛋白相互作用，是连接神经素-神经素- shank通路的主要功能桥梁，与自闭症谱系障碍有关。作者在PSD-95缺失小鼠（Dlg4−/−）中描述了与自闭症谱系障碍相关的行为、树突和分子表型异常。来自小鼠的数据鉴定了人类DLG4的单核苷酸多态性（snp），并使用功能和结构神经成像技术检查了这些变异与正常人群中威廉姆斯综合征神经特征之间的关系。Dlg4−/−表现出重复行为增加，沟通和社交行为异常，运动协调受损，应激反应和焦虑相关反应增加。Dlg4−/−具有杏仁核树突棘的细微畸形和各种突触基因的前脑表达改变，包括Cyln2，它调节细胞骨架动力学，是威廉姆斯综合征的候选基因。两种人类DLG4 snp的变异与顶内沟体积减少和皮质-杏仁核偶联异常之间存在显著关联，这两者都是威廉姆斯综合征的特征。这些发现表明，小鼠的Dlg4基因破坏会产生一系列复杂的与自闭症谱系障碍和威廉姆斯综合征相关的行为和分子异常。该研究提供了人类DLG4基因变异与威廉姆斯综合征关键神经内表型之间的初步联系，或许还提供了更普遍的情绪和社会过程的皮质-杏仁核调节。
Research is increasingly linking autism spectrum disorders and other neurodevelopmental disorders to synaptic abnormalities (“synaptopathies”). PSD-95 (postsynaptic density-95, DLG4) orchestrates protein-protein interactions at excitatory synapses and is a major functional bridge interconnecting a neurexin-neuroligin-SHANK pathway implicated in autism spectrum disorders. The authors characterized behavioral, dendritic, and molecular phenotypic abnormalities relevant to autism spectrum disorders in mice with PSD-95 deletion (Dlg4−/−). The data from mice led to the identification of single-nucleotide polymorphisms (SNPs) in human DLG4 and the examination of associations between these variants and neural signatures of Williams’ syndrome in a normal population, using functional and structural neuroimaging. Dlg4−/− showed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses. Dlg4−/− had subtle dysmorphology of amygdala dendritic spines and altered forebrain expression of various synaptic genes, including Cyln2, which regulates cytoskeletal dynamics and is a candidate gene for Williams’ syndrome. A significant association was observed between variations in two human DLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling, both of which characterize Williams’ syndrome. These findings demonstrate that Dlg4 gene disruption in mice produces a complex range of behavioral and molecular abnormalities relevant to autism spectrum disorders and Williams’ syndrome. The study provides an initial link between human DLG4 gene variation and key neural endophenotypes of Williams’ syndrome and perhaps cortico-amygdala regulation of emotional and social processes more generally.
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DOI：
10.1523/jneurosci.4457-06.2007
发表时间：
2007-03-07
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Cuthbert PC;Stanford LE;Coba MP;Ainge JA;Fink AE;Opazo P;Delgado JY;Komiyama NH;O'Dell TJ;Grant SG
通讯作者：
Grant SG
影响因子：
5.3
作者：
Hung, Albert Y.;Futai, Kensuke;Sheng, Morgan
通讯作者：
Sheng, Morgan
影响因子：
16.2
作者：
Hoeffer, Charles A.;Tang, Wei;Klann, Eric
通讯作者：
Klann, Eric
影响因子：
2.5
作者：
McFarlane, H. G.;Kusek, G. K.;Crawley, J. N.
通讯作者：
Crawley, J. N.
影响因子：
5.7
作者：
Hariri, AR;Tessitore, A;Weinberger, DR
通讯作者：
Weinberger, DR