Deletion of α-neurexin II results in autism-related behaviors in mice.
Deletion of α-neurexin II results in autism-related behaviors in mice.
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DOI：
10.1038/tp.2014.123
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发表时间：
2014-11-25
影响因子：
6.8
通讯作者：
Clapcote SJ
中科院分区：
文献类型：
--
作者：
Dachtler J;Glasper J;Cohen RN;Ivorra JL;Swiffen DJ;Jackson AJ;Harte MK;Rodgers RJ;Clapcote SJ
自闭症是一种常见的、经常致残的神经发育障碍，具有很强的遗传基础。人类遗传学研究发现，NRXN 2基因的外显子发生突变，该基因编码突触粘附蛋白α-neurexin II（Nrxn 2 α），在两个不相关的自闭症个体中，但NRXN 2与该疾病之间的因果关系尚不清楚。为了开始检验Nrxn 2 α缺陷导致自闭症症状的假设，我们采用了Nrxn 2 α敲除（KO）小鼠，其在体内遗传模拟了Nrxn 2 α缺陷。我们报告说，Nrxn 2 α基因敲除小鼠在暴露于新的同种时，表现出社交能力和社会记忆的缺陷。在探索性活动试验中，与野生型同窝小鼠相比，Nrxn 2 α KO小鼠表现出焦虑样表型，在开放视野中具有趋触性，在高架十字迷宫的开放臂中花费的时间较少，在出现试验的封闭环境中花费的时间较多，探索新物体花费的时间较少。然而，Nrxn 2 α KO小鼠在前脉冲抑制或被动回避学习方面没有表现出任何明显的变化。额叶皮层和海马的实时PCR分析显示，参与兴奋性和抑制性传递的蛋白质编码基因的mRNA水平显着下降。蛋白质表达的定量显示，由Stxbp 1编码的Munc 18 -1在Nrxn 2 α KO小鼠的海马中显著降低，这表明突触前囊泡释放的缺陷。我们的研究结果证明了Nrxn 2 α的缺失在小鼠自闭症相关行为的发生中的因果作用。
Autism is a common and frequently disabling neurodevelopmental disorder with a strong genetic basis. Human genetic studies have discovered mutations disrupting exons of the NRXN2 gene, which encodes the synaptic adhesion protein α-neurexin II (Nrxn2α), in two unrelated individuals with autism, but a causal link between NRXN2 and the disorder remains unclear. To begin to test the hypothesis that Nrxn2α deficiency contributes to the symptoms of autism, we employed Nrxn2α knockout (KO) mice that genetically model Nrxn2α deficiency in vivo. We report that Nrxn2α KO mice displayed deficits in sociability and social memory when exposed to novel conspecifics. In tests of exploratory activity, Nrxn2α KO mice displayed an anxiety-like phenotype in comparison with wild-type littermates, with thigmotaxis in an open field, less time spent in the open arms of an elevated plus maze, more time spent in the enclosure of an emergence test and less time spent exploring novel objects. However, Nrxn2α KO mice did not exhibit any obvious changes in prepulse inhibition or in passive avoidance learning. Real-time PCR analysis of the frontal cortex and hippocampus revealed significant decreases in the mRNA levels of genes encoding proteins involved in both excitatory and inhibitory transmission. Quantification of protein expression revealed that Munc18-1, encoded by Stxbp1, was significantly decreased in the hippocampus of Nrxn2α KO mice, which is suggestive of deficiencies in presynaptic vesicular release. Our findings demonstrate a causal role for the loss of Nrxn2α in the genesis of autism-related behaviors in mice.
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影响因子：
5.3
作者：
Gauthier J;Siddiqui TJ;Huashan P;Yokomaku D;Hamdan FF;Champagne N;Lapointe M;Spiegelman D;Noreau A;Lafrenière RG;Fathalli F;Joober R;Krebs MO;DeLisi LE;Mottron L;Fombonne E;Michaud JL;Drapeau P;Carbonetto S;Craig AM;Rouleau GA
通讯作者：
Rouleau GA
DOI：
10.1002/ajmg.b.31063
发表时间：
2010-06-05
影响因子：
2.8
作者：
Ching, Michael S. L.;Shen, Yiping;Tan, Wen-Hann;Jeste, Shafali S.;Morrow, Eric M.;Chen, Xiaoli;Mukaddes, Nahit M.;Yoo, Seung-Yun;Hanson, Ellen;Hundley, Rachel;Austin, Christina;Becker, Ronald E.;Berry, Gerard T.;Driscoll, Katherine;Engle, Elizabeth C.;Friedman, Sandra;Gusella, James F.;Hisama, Fuki M.;Irons, Mira B.;Lafiosca, Tina;LeClair, Elaine;Miller, David T.;Neessen, Michael;Picker, Jonathan D.;Rappaport, Leonard;Rooney, Cynthia M.;Sarco, Dean P.;Stoler, Joan M.;Walsh, Christopher A.;Wolff, Robert R.;Zhang, Ting;Nasir, Ramzi H.;Wu, Bai-Lin
通讯作者：
Wu, Bai-Lin
影响因子：
4.8
作者：
Biederer, T;Südhof, TC
通讯作者：
Südhof, TC
影响因子：
10.6
作者：
Carper, RA;Courchesne, E
通讯作者：
Courchesne, E
神经1α基因敲除小鼠的社交行为改变类似于神经发育障碍中的核心症状。
影响因子：
3.7
作者：
Grayton HM;Missler M;Collier DA;Fernandes C
通讯作者：
Fernandes C