Palmitoylation of cdc42 Promotes Spine Stabilization and Rescues Spine Density Deficit in a Mouse Model of 22q11.2 Deletion Syndrome
Palmitoylation of cdc42 Promotes Spine Stabilization and Rescues Spine Density Deficit in a Mouse Model of 22q11.2 Deletion Syndrome
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DOI：
10.1093/cercor/bhw183
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发表时间：
2017-07-01
期刊：
影响因子：
3.7
通讯作者：
Muller, D.
中科院分区：
文献类型：
--
作者：
Moutin, E.;Nikonenko, I.;Muller, D.
22q11.2缺失综合征（22 q11 DS）与学习和认知功能障碍以及患精神分裂症的高风险有关。树突棘的可塑性与认知密切相关，这一点越来越清楚。因此，了解认知障碍中的基因如何影响突触网络是现代生物学的一个主要挑战。几项研究指出，在22 q11 DS转基因小鼠模型中存在棘密度缺陷。使用LgDel小鼠模型，我们首先使用电子显微镜在不同阶段量化脊柱缺陷。接下来，我们对LgDel小鼠的海马器官型培养物进行了几天的重复共聚焦成像。我们没有发现每日脊柱形成和脊柱消除之间的比例失衡，但脊柱预期寿命降低。我们通过过表达ZDHHC 8棕榈酰转移酶（其基因属于LgDel微缺失）来纠正这种受损的脊柱稳定过程。其底物之一，cdc 42脑特异性变体，在组成型活性形式（cdc 42-palm-CA）下的过表达导致了相同的结果。最后，我们可以拯救脊柱密度在体内，在成年LgDel小鼠，通过注射表达cdc 42-palm-CA的载体的幼崽。本研究揭示了ZDHHC 8-cdc 42-palm分子通路在突触后结构可塑性中的新作用，为支持精神分裂症的连接障碍假说提供了新的证据。
22q11.2 deletion syndrome (22q11DS) is associated with learning and cognitive dysfunctions and a high risk of developing schizophrenia. It has become increasingly clear that dendritic spine plasticity is tightly linked to cognition. Thus, understanding how genes involved in cognitive disorders affect synaptic networks is a major challenge of modern biology. Several studies have pointed to a spine density deficit in 22q11DS transgenic mice models. Using the LgDel mouse model, we first quantified spine deficit at different stages using electron microscopy. Next we performed repetitive confocal imaging over several days on hippocampal organotypic cultures of LgDel mice. We show no imbalanced ratio between daily spine formation and spine elimination, but a decreased spine life expectancy. We corrected this impaired spine stabilization process by overexpressing ZDHHC8 palmitoyltransferase, whose gene belongs to the LgDel microdeletion. Overexpression of one of its substrates, the cdc42 brain-specific variant, under a constitutively active form (cdc42-palm-CA) led to the same result. Finally, we could rescue spine density in vivo, in adult LgDel mice, by injecting pups with a vector expressing cdc42-palm-CA. This study reveals a new role of ZDHHC8-cdc42-palm molecular pathway in postsynaptic structural plasticity and provides new evidence in favor of the dysconnectivity hypothesis for schizophrenia.