Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice.
Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice.
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DOI：
10.1126/scitranslmed.3002627
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发表时间：
2011-10-05
影响因子：
17.1
通讯作者：
Anderson MP
中科院分区：
文献类型：
--
作者：
Smith SE;Zhou YD;Zhang G;Jin Z;Stoppel DC;Anderson MP
自闭症谱系障碍患者的特征是社会互动受损，沟通减少，重复行为增加。这种疾病有很大的遗传成分，最近的研究表明，在一些个体中频繁的基因组拷贝数变异（CNVs）。一种常见的CNV发生在1%到3%的自闭症患者中，即母亲15 q11 -13重复（dup 15）和三倍（等双着丝粒染色体，idic 15），它影响了几个被认为是自闭症行为特征基础的基因。为了测试这一点，我们将其中一个基因的剂量增加了两倍，泛素蛋白连接酶Ube 3a，它只在成熟神经元中从母体等位基因中表达，并在小鼠中重建了三个核心自闭症特征：社交互动缺陷，沟通受损和重复刻板行为增加。这些孤独症特征的发生率依赖于Ube 3a基因拷贝数。在Ube 3a基因剂量增加的动物中，谷氨酸能，但不是GABA能，突触传递受到抑制，这是由于突触前释放概率降低，突触谷氨酸浓度降低和突触后动作电位耦合。这些结果表明，Ube 3a基因的剂量可能有助于与母亲15 q11 -13重复的个体的自闭症特征，并支持E3 A泛素连接酶基因剂量增加导致兴奋性突触传递减少的想法。
People with autism spectrum disorder are characterized by impaired social interaction, reduced communication, and increased repetitive behaviors. The disorder has a substantial genetic component, and recent studies have revealed frequent genome copy number variations (CNVs) in some individuals. A common CNV that occurs in 1 to 3% of those with autism—maternal 15q11-13 duplication (dup15) and triplication (isodicentric extranumerary chromosome, idic15)—affects several genes that have been suggested to underlie autism behavioral traits. To test this, we tripled the dosage of one of these genes, the ubiquitin protein ligase Ube3a, which is expressed solely from the maternal allele in mature neurons, and reconstituted the three core autism traits in mice: defective social interaction, impaired communication, and increased repetitive stereotypic behavior. The penetrance of these autism traits depended on Ube3a gene copy number. In animals with increased Ube3a gene dosage, glutamatergic, but not GABAergic, synaptic transmission was suppressed as a result of reduced presynaptic release probability, synaptic glutamate concentration, and postsynaptic action potential coupling. These results suggest that Ube3a gene dosage may contribute to the autism traits of individuals with maternal 15q11-13 duplication and support the idea that increased E3A ubiquitin ligase gene dosage results in reduced excitatory synaptic transmission.
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影响因子：
6.2
作者：
Bozdagi O;Sakurai T;Papapetrou D;Wang X;Dickstein DL;Takahashi N;Kajiwara Y;Yang M;Katz AM;Scattoni ML;Harris MJ;Saxena R;Silverman JL;Crawley JN;Zhou Q;Hof PR;Buxbaum JD
通讯作者：
Buxbaum JD
影响因子：
2.6
作者：
Ehret, G
通讯作者：
Ehret, G
影响因子：
14.9
作者：
Landers, M;Bancescu, DL;Lalande, M
通讯作者：
Lalande, M
影响因子：
2
作者：
Dennis, NR;Veltman, MWM;Thomas, NS
通讯作者：
Thomas, NS
影响因子：
3.5
作者：
Kashiwagi, A;Meguro, M;Oshimura, M
通讯作者：
Oshimura, M