Deficiency of the palmitoyl acyltransferase ZDHHC7 impacts brain and behavior of mice in a sex-specific manner
Deficiency of the palmitoyl acyltransferase ZDHHC7 impacts brain and behavior of mice in a sex-specific manner
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DOI：
10.1007/s00429-019-01898-6
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发表时间：
2019-07-01
影响因子：
3.1
通讯作者：
Zhang, Weiqi
中科院分区：
文献类型：
--
作者：
Hohoff, Christa;Zhang, Mingyue;Zhang, Weiqi
棕榈酰酰基转移酶ZDHHC 7属于DHHC家族，负责棕榈酸与靶蛋白的共价连接（棕榈酰化）。在突触蛋白中，其主要靶点是性类固醇受体，如雌激素受体。当棕榈酰化时，这些偶联到膜微结构域并引起非基因组快速反应。这种耦合尤其在影响结构、功能和行为结果的皮质边缘脑区域中发现。到目前为止，ZDHHC 7的功能作用尚未在此背景下进行研究。为了直接分析ZDHHC 7对大脑解剖结构、微观结构、连接性、功能和行为的影响，我们产生了一种突变小鼠，其中Zdhhc 7基因组成性失活。使用行为测试、电生理学、蛋白质分析和基于扩散张量的纤维束成像的神经成像，将雄性和雌性Zdhhc 7（-/-）小鼠与野生型小鼠进行表型比较。Zdhhc 7缺陷损害兴奋性传递，在海马Schaffer侧支CA 1突触的突触可塑性，和海马结构连接在两种性别以类似的方式。对两种性别，但以不同的方式出现在内侧前额叶皮层突触传递和海马的微观结构。最后，Zdhhc 7缺乏症只影响女性的焦虑相关行为。我们的数据证明了Zdhhc 7在小鼠中以性别相关的方式在系统水平上组装适当的大脑结构，功能和行为的重要性。考虑到性别特异性在人类和相关精神障碍中的突出作用，Zdhhc 7（-/-）小鼠可能为深入研究潜在的性别特异性改变机制提供了一个有希望的模型。
The palmitoyl acyltransferase ZDHHC7 belongs to the DHHC family responsible for the covalent attachment of palmitic acid (palmitoylation) to target proteins. Among synaptic proteins, its main targets are sex steroid receptors such as the estrogen receptors. When palmitoylated, these couple to membrane microdomains and elicit non-genomic rapid responses. Such coupling is found particularly in cortico-limbic brain areas which impact structure, function, and behavioral outcomes. Thus far, the functional role of ZDHHC7 has not been investigated in this context. To directly analyze an impact of ZDHHC7 on brain anatomy, microstructure, connectivity, function, and behavior, we generated a mutant mouse in which the Zdhhc7 gene is constitutively inactivated. Male and female Zdhhc7(-/-) mice were phenotypically compared with wild-type mice using behavioral tests, electrophysiology, protein analyses, and neuroimaging with diffusion tensor-based fiber tractography. Zdhhc7-deficiency impaired excitatory transmission, synaptic plasticity at hippocampal Schaffer collateral CA1 synapses, and hippocampal structural connectivity in both sexes in similar manners. Effects on both sexes but in different manners appeared in medial prefrontal cortical synaptic transmission and in hippocampal microstructures. Finally, Zdhhc7-deficiency affected anxiety-related behaviors exclusively in females. Our data demonstrated the importance of Zdhhc7 for assembling proper brain structure, function, and behavior on a system level in mice in a sex-related manner. Given the prominent role of sex-specificity also in humans and associated mental disorders, Zdhhc7(-/-) mice might provide a promising model for in-depth investigation of potentially underlying sex-specifically altered mechanisms.