Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development.
Interaction between autism-linked MDGAs and neuroligins suppresses inhibitory synapse development.
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DOI：
10.1083/jcb.201206028
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发表时间：
2013-02-04
期刊：
影响因子：
--
通讯作者：
Craig AM
中科院分区：
文献类型：
--
作者：
Pettem KL;Yokomaku D;Takahashi H;Ge Y;Craig AM
选择性抑制抑制性突触--对兴奋性突触没有影响--是自闭症与精神分裂症相关蛋白MDGA1和神经连接蛋白-2通过影响神经连接蛋白-神经尿素素途径相互作用的结果。MDGA(含MAM结构域的糖基磷脂酰肌醇锚定)的罕见变异，包括多个蛋白质截断缺失，与自闭症和精神分裂症有关，但这些基因的功能尚不清楚。在这里，我们发现MDGA1和MDGA2与神经连接蛋白-2抑制性突触组织蛋白结合，这也与神经发育障碍有关。MDGA1通过抑制神经连接蛋白-2与Neuresin的相互作用，在不改变神经连接蛋白-2表面转运的情况下，抑制神经连接蛋白-2的突触促进活性。MDGA的结合和突触生成活性的抑制是对神经连接素-2而不是神经连接素-1兴奋性突触组织者的选择性。在培养的大鼠海马神经元中过表达MDGA1可降低抑制性突触密度，但不改变兴奋性突触密度。此外，RNAi介导的MDGA1基因敲除选择性地增加了抑制性突触密度，而不是兴奋性突触密度。这些结果表明，MDGA1是为数不多的对突触发育具有独特选择性的突触发育的负调控因子之一。这些结果还将MDGA置于与神经发育障碍有关的神经尿素素-神经连接素突触通路中，并支持抑制性和兴奋性突触之间的失衡可能导致这些障碍的观点。
Selective suppression of inhibitory synapses—with no effect on excitatory synapses—results from interaction of the autism- and schizophrenia-associated proteins MDGA1 and neuroligin-2 through effects on the neuroligin–neurexin pathway. Rare variants in MDGAs (MAM domain–containing glycosylphosphatidylinositol anchors), including multiple protein-truncating deletions, are linked to autism and schizophrenia, but the function of these genes is poorly understood. Here, we show that MDGA1 and MDGA2 bound to neuroligin-2 inhibitory synapse–organizing protein, also implicated in neurodevelopmental disorders. MDGA1 inhibited the synapse-promoting activity of neuroligin-2, without altering neuroligin-2 surface trafficking, by inhibiting interaction of neuroligin-2 with neurexin. MDGA binding and suppression of synaptogenic activity was selective for neuroligin-2 and not neuroligin-1 excitatory synapse organizer. Overexpression of MDGA1 in cultured rat hippocampal neurons reduced inhibitory synapse density without altering excitatory synapse density. Furthermore, RNAi-mediated knockdown of MDGA1 selectively increased inhibitory but not excitatory synapse density. These results identify MDGA1 as one of few identified negative regulators of synapse development with a unique selectivity for inhibitory synapses. These results also place MDGAs in the neurexin–neuroligin synaptic pathway implicated in neurodevelopmental disorders and support the idea that an imbalance between inhibitory and excitatory synapses may contribute to these disorders.
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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
影响因子：
56.9
作者：
Biederer, T;Sara, Y;Südhof, TC
通讯作者：
Südhof, TC
DOI：
10.1073/pnas.1006946108
发表时间：
2011-02-15
影响因子：
11.1
作者：
Hoon, Mrinalini;Soykan, Tolga;Varoqueaux, Frederique
通讯作者：
Varoqueaux, Frederique
影响因子：
56.9
作者：
Chih, B;Engelman, H;Scheiffele, P
通讯作者：
Scheiffele, P
影响因子：
5.3
作者：
Hines, Rochelle M.;Wu, Longjun;El-Husseini, Alaa
通讯作者：
El-Husseini, Alaa