Einat H, Yuan P, Manji HK. 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. Behav Brain Res 165: 172-180

College of Pharmacy, Duluth, University of Minnesota, 376 Kirby Plaza, 1208 Kirby Drive, Duluth, MN 55812, USA.
Behavioural Brain Research (Impact Factor: 3.03). 01/2006; 165(2):172-80. DOI: 10.1016/j.bbr.2005.06.012
Source: PubMed


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.

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    • "In another point of view, Einat et al. (2005) have reported that Bcl2 gene deletion in mice resulted in increased anxiety-like behavior, specifically, with insignificant impact on the gross behavioral. Otherwise, they discussed an apoptotic-independent rout for Bcl2 anti-anxiety activity (Einat et al. 2005). Our data suggest consistent conclusion that Nrf2 silencing upregulated caspase-3 cleavage, an irreversible step in apoptosis induction, along with a significant elevation in Bax/Bcl2 ratio. "
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    ABSTRACT: Anxiety-related disorders are complex illnesses that underlying molecular mechanisms of these complicated emotional disorders are poorly understood. Nuclear factor erythroid 2-related factor 2 (Nrf2) is the most important regulator of the antioxidant defense system. Its protective actions are not only limited to antioxidative transactivation, but also plays important roles in encountering various physiological and pathological stresses. In this study, we evaluated whether silencing of Nrf2 plays a role in development of anxiety-related behavior. In this regard, we exerted small interfering RNA (siRNA) targeting Nrf2 in dorsal third ventricle and subsequently examined the effect of this silencing on anxiety-related behavior along with supposed molecular mechanisms. Therefore, we evaluated apoptotic markers and mitochondrial electron transport chain (ETC) activity in three brain regions: hippocampus, amygdala, and prefrontal cortex. Based on our result, Nrf2-silenced rats exhibited greater anxiety-like behavior compared to control group. Furthermore, Nrf2 silencing increased activity of ETC complexes. Also, Bax/Bcl2 ratio of all mentioned areas of the brain and cleavage of caspase-3 in hippocampus increased in Nrf2 silenced group, however, with a distinct pattern.
    Journal of Molecular Neuroscience 07/2014; 55(2). DOI:10.1007/s12031-014-0370-z · 2.34 Impact Factor
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    • "An unexpected finding was that the suicides of persons with a primary diagnosis of anxiety disorder occurred at an average altitude greater than that of suicides in MDD or schizophrenia. The results of animal studies by Einat et al. [42] and others [43] [44] provide support for the involvement of mitochondrial function in anxiety disorders. Very recent proteomic and metabolomic findings implicate a previously unrecognized role for mitochondria in modulating anxiety-related behaviors [43]. "
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    • "Third, mitochondria-targeted antioxidant SkQ1 has been associated with decreased expression of anxiety behaviors in rats (Stefanova et al. 2010). Finally, mutant mice with reduced function of Bcl-2, a key modulator of mitochondrial function, demonstrate increased anxiety behavior (Einat et al. 2005). Exposure to cigarettes can lead to mitochondrial dysfunction (Miro et al. 1999; Anbarasi et al. 2005b), as demonstrated by increased levels of cholesterol, lipid peroxides and increased cholesterol/phospholipid ratio, in conjunction with decreased mitochondrial enzymes in those exposed to cigarette smoke. "
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