Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice.
Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice.
复制标题
14-3-3蛋白的抑制导致小鼠中与精神分裂症相关的行为表型和突触缺陷。
DOI：
10.1016/j.biopsych.2015.02.015
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发表时间：
2015-09-15
影响因子：
10.6
通讯作者：
Zhou Y
中科院分区：
文献类型：
--
作者：
Foote M;Qiao H;Graham K;Wu Y;Zhou Y
14-3-3 蛋白家族参与多个关键神经元过程的调节。先前的人类和动物研究表明 14-3-3 失调与精神分裂症之间存在关联。我们表征了在大脑中表达独立于亚型的 14-3-3 抑制肽的转基因小鼠的行为和功能变化。我们最近发现 14-3-3 功能性基因敲除小鼠 (FKO) 表现出联想学习和记忆障碍。在这里，我们报告这些 14-3-3 FKO 小鼠表现出与精神分裂症核心症状相对应的其他行为缺陷。这些行为缺陷可能归因于 14-3-3 FKO 小鼠多个神经传递系统的改变。特别是，抑制 14-3-3 蛋白会导致前脑兴奋性神经元的树突复杂性和棘密度降低，这可能是 14-3-3 FKO 小鼠前额皮质突触突触连接性改变的基础。在分子水平上，这种树突棘缺陷可能源于肌动蛋白动力学失调，这是由于磷酸化丝切蛋白的 14-3-3 依赖性调节被破坏所致。总的来说，我们的数据提供了 14-3-3 功能障碍、突触改变和精神分裂症相关行为缺陷之间的联系。
The 14-3-3 family of proteins is implicated in the regulation of several key neuronal processes. Previous human and animal studies have suggested an association between 14-3-3 dysregulation and schizophrenia. We characterized the behavioral and functional changes in the transgenic mice that express an isoform-independent 14-3-3 inhibitor peptide in the brain. We have recently shown that the 14-3-3 functional knockout mice (FKO) exhibit impairments in associative learning and memory. Here, we report that these 14-3-3 FKO mice display other behavioral deficits which correspond to the core symptoms of schizophrenia. These behavioral deficits may be attributed to alterations in multiple neurotransmission systems in the 14-3-3 FKO mice. Particularly, inhibition of 14-3-3 proteins results in a reduction of dendritic complexity and spine density in forebrain excitatory neurons, which may underlie the altered synaptic connectivity in the prefrontal cortical synapse of the 14-3-3 FKO mice. At the molecular level, this dendritic spine defect may stem from dysregulated actin dynamics due to a disruption of the 14-3-3-dependent regulation of phosphorylated cofilin. Collectively, our data provide a link between 14-3-3 dysfunction, synaptic alterations, and schizophrenia-associated behavioral deficits.