Increased anxiety-like behaviors and mitochondrial dysfunction in mice with targeted mutation of the Bcl-2 gene: Further support for the involvement of mitochondrial function in anxiety disorders
Increased anxiety-like behaviors and mitochondrial dysfunction in mice with targeted mutation of the Bcl-2 gene: Further support for the involvement of mitochondrial function in anxiety disorders
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DOI：
10.1016/j.bbr.2005.06.012
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发表时间：
2005-12-07
影响因子：
2.7
通讯作者：
Manji, HK
中科院分区：
文献类型：
--
作者：
Einat, H;Yuan, P;Manji, HK
越来越多的证据表明，焦虑症与细胞可塑性和恢复力的受损有关。随着我们对焦虑症神经生物学基础的理解取得这些进展，线粒体在调节综合CNS功能中发挥的各种功能也越来越受到重视。新出现的数据表明，线粒体Ca 2+封存在调节各种神经解剖区域的突触可塑性方面发挥着关键作用，包括那些与焦虑症病理生理学有关的区域。此外，外周线粒体苯二氮卓受体的激活导致大鼠焦虑减少。线粒体功能的主要调节剂之一是嵌入线粒体内膜中的Bcl-2蛋白。Bcl-2过表达增加线粒体Ca 2+摄取能力和对呼吸的Ca 2+抑制的抗性，并且Bcl-2的上调增加线粒体的最大摄取能力。因此，我们探索了Bcl-2在线粒体功能和情感障碍之间的关联中的意义，在情感障碍和焦虑障碍模型中测试Bcl-2杂合子小鼠，突变小鼠的线粒体Bcl-2水平降低，尽管它们没有明显的行为异常，但它们表现出焦虑样行为的显著增加。与WT对照组相比，Bcl-2杂合子小鼠在开放场地中心花费的时间较少，在“出现测试”中在围栏外花费的时间较少，不太可能探索黑色/白色盒子的透明部分或高架十字迷宫的开放臂。突变小鼠在运动或强迫游泳测试中的抑郁样行为的测量结果与WT没有差异，这表明Bcl-2对焦虑样行为有特定的影响，因此我们的研究表明，Bcl-2可能是焦虑症的关键因素，其影响可能源于其在线粒体中的作用。(c)2005年由Elsevier B. V.出版
There is growing evidence that anxiety disorders are associated with impairments of cellular plasticity and resilience. Paralleling these advances in our understanding of the neurobiologic underpinnings of anxiety disorders is the growing appreciation of the diverse functions that mitochondria play in regulating integrated CNS function. The emerging data suggest that mitochondrial Ca2+ sequestration has a key role in modulating the tone of synaptic plasticity in a variety of neuroanatomical regions, including those implicated in the pathophysiology of anxiety disorders. Furthermore, activation of peripheral mitochondrial benzodiazepine receptors resulted in reduced anxiety in rats. One of the major modulators of mitochondrial function is Bcl-2 proteins imbedded in the inner mitochondrial membrane. Bcl-2 overexpression increases mitochondria Ca2+ uptake capacity and resistance to Ca2+-inhibition of respiration and upregulation of Bcl-2 increases maximal uptake capacity of mitochondria. We have, therefore, explored the significance of Bcl-2 in the association between mitochondrial function and affective disorders testing Bcl-2 heterozygote mice in models of affective and anxiety disorders.Mutant mice have reduced mitochondrial Bcl-2 levels, and although they have no gross behavioral abnormalities, they demonstrate a significant increase of anxiety-like behaviors. Bcl-2 heterozygote mice spent less time in the center of an open field, spent less time outside an enclosure in the "emergence test", were less likely to explore the transparent part of a black/white box or the open arms of an elevated plus maze compared with WT controls. Mutant mice did not differ from WT in measures of locomotion or in the forced swim test for depression-like behavior suggesting a specific effect on anxiety-like behaviors.Our study, therefore demonstrates that Bcl-2 may be a key factor in anxiety disorders and that its effects may possibly originate from its role in the mitochondria. (c) 2005 Published by Elsevier B.V.