1] Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer-Sheva, Israel [2] Psychiatry Research Unit, Ben-Gurion University of the Negev, Beer-Sheva, Israel [3] Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
1] Psychiatry Research Unit, Ben-Gurion University of the Negev, Beer-Sheva, Israel [2] Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel [3] Mental Health Center, Beer-Sheva, Israel.
Neuropsychopharmacology. 2014 Jan;39(2):319-28. doi: 10.1038/npp.2013.194. Epub 2013 Aug 8.
The inositol-depletion hypothesis proposes that lithium attenuates phosphatidylinositol signaling. Knockout (KO) mice of two genes (IMPA1 or Slc5a3), each encoding for a protein related to inositol metabolism, were studied in comparison with lithium-treated mice. Since we previously demonstrated that these KO mice exhibit a lithium-like neurochemical and behavioral phenotype, here we searched for pathways that may mediate lithium's/the KO effects. We performed a DNA-microarray study searching for pathways affected both by chronic lithium treatment and by the KO of each of the genes. The data were analyzed using three different bioinformatics approaches. We found upregulation of mitochondria-related genes in frontal cortex of lithium-treated, IMPA1 and Slc5a3 KO mice. Three out of seven genes differentially expressed in all three models, Cox5a, Ndufs7, and Ndufab, all members of the mitochondrial electron transfer chain, have previously been associated with bipolar disorder and/or lithium treatment. Upregulation of the expression of these genes was verified by real-time PCR. To further support the link between mitochondrial function and lithium's effect on behavior, we determined the capacity of chronic low-dose rotenone, a mitochondrial respiratory chain complex I inhibitor, to alter lithium-induced behavior as measured by the forced-swim and the amphetamine-induced hyperlocomotion paradigms. Rontenone treatment counteracted lithium's effect on behavior, supporting the proposition suggested by the bioinformatics analysis for a mitochondrial function involvement in behavioral effects of lithium mediated by inositol metabolism alterations.The results provide support for the notion that mitochondrial dysfunction is linked to bipolar disorder and can be ameliorated by lithium. The phenotypic similarities between lithium-treated wild-type mice and the two KO models suggest that lithium may affect behavior by altering inositol metabolism.
肌醇耗竭假说提出，锂可减弱磷脂酰肌醇信号。两种基因（IMPAl 或 Slc5a3）的敲除（KO）小鼠，分别编码与肌醇代谢相关的蛋白质，与锂处理的小鼠进行了比较。由于我们之前证明这些 KO 小鼠表现出类似锂的神经化学和行为表型，因此我们在这里寻找可能介导锂/ KO 效应的途径。我们进行了 DNA 微阵列研究，以寻找受慢性锂处理和每种基因 KO 影响的途径。使用三种不同的生物信息学方法分析数据。我们发现锂处理、IMPAl 和 Slc5a3 KO 小鼠前额叶皮质中线粒体相关基因的上调。在所有三种模型中差异表达的七个基因中的三个，Cox5a、Ndufs7 和 Ndufab，都是线粒体电子传递链的成员，以前与双相情感障碍和/或锂治疗有关。通过实时 PCR 验证了这些基因表达上调。为了进一步支持线粒体功能与锂对行为的影响之间的联系，我们确定了慢性低剂量鱼藤酮（一种线粒体呼吸链复合物 I 抑制剂）改变锂诱导行为的能力，如强迫游泳和安非他命诱导的过度活跃范式。Rotenone 处理抵消了锂对行为的影响，支持生物信息学分析提出的关于线粒体功能参与锂通过改变肌醇代谢介导的行为效应的假设。结果为线粒体功能障碍与双相情感障碍有关的观点提供了支持，并且可以通过锂来改善。锂处理的野生型小鼠和两种 KO 模型之间的表型相似性表明，锂可能通过改变肌醇代谢来影响行为。
