NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse
NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse
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DOI：
10.1038/mp.2015.42
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发表时间：
2015-09-01
影响因子：
11
通讯作者：
Rosario, M.
中科院分区：
文献类型：
--
作者：
Schuster, S.;Rivalan, M.;Rosario, M.
神经精神发育障碍，如自闭症谱系障碍（ASD）和精神分裂症，通常以社会行为的改变为特征，并与异常的树突棘和突触发育有关。在这里，我们表明，使用基因工程小鼠，Cdc 42 GTP酶激活的多适配蛋白，NOMA-GAP，调节自闭症样的社会行为在小鼠，以及树突棘和突触的发展。令人惊讶的是，我们无法恢复脊柱形态或孤独症相关的社会行为NOMA-GAP缺陷的动物通过Cre介导的Cdc 42单独删除。脊柱形态可以通过野生型NOMA-GAP或缺乏RhoGAP结构域的NOMA-GAP突变体的再表达在体内恢复，这表明涉及其他信号传导功能。事实上，我们表明NOMA-GAP直接与几种MAGUK（膜相关鸟苷酸激酶）蛋白相互作用，这调节NOMA-GAP对Cdc 42的活性。此外，我们证明，NOMA-GAP是PSD-95在新皮层的主要调节。NOMA-GAP的缺失导致PSD-95的丝氨酸295磷酸化的强烈上调，并且还导致其亚细胞错误定位。这与表面α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的显著丧失和突触传递缺陷有关，从而为NOMA-GAP缺失时的自闭症样社会行为提供了分子基础。
Neuropsychiatric developmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia, are typically characterized by alterations in social behavior and have been linked to aberrant dendritic spine and synapse development. Here we show, using genetically engineered mice, that the Cdc42 GTPase-activating multiadaptor protein, NOMA-GAP, regulates autism-like social behavior in the mouse, as well as dendritic spine and synapse development. Surprisingly, we were unable to restore spine morphology or autism-associated social behavior in NOMA-GAP-deficient animals by Cre-mediated deletion of Cdc42 alone. Spine morphology can be restored in vivo by re-expression of wild-type NOMA-GAP or a mutant of NOMA-GAP that lacks the RhoGAP domain, suggesting that other signaling functions are involved. Indeed, we show that NOMA-GAP directly interacts with several MAGUK (membrane-associated guanylate kinase) proteins, and that this modulates NOMA-GAP activity toward Cdc42. Moreover, we demonstrate that NOMA-GAP is a major regulator of PSD-95 in the neocortex. Loss of NOMA-GAP leads to strong upregulation of serine 295 phosphorylation of PSD-95 and moreover to its subcellular mislocalization. This is associated with marked loss of surface alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and defective synaptic transmission, thereby providing a molecular basis for autism-like social behavior in the absence of NOMA-GAP.