IMPA1 is essential for embryonic development and lithium-like pilocarpine sensitivity
IMPA1 is essential for embryonic development and lithium-like pilocarpine sensitivity
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DOI：
10.1038/sj.npp.1301431
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发表时间：
2008-02-01
影响因子：
7.6
通讯作者：
Moechars, Dieder
中科院分区：
文献类型：
--
作者：
Cryns, Kim;Shamir, Alon;Moechars, Dieder
过去 50 年来，锂盐一直是双相情感障碍的标准药物治疗方法；然而，锂发挥治疗作用的分子靶点仍未确定。我们对具有功能障碍的 IMPA1 基因 (IMPA1(-/-)) 的小鼠的表型进行了表征，以研究 IMPA1 的体内生理功能，更具体地说，它作为介导锂依赖性生理效应的分子靶标的潜在作用。纯合子 IMPA1(-/-) 小鼠在交配后第 9.5 天至 10.5 天之间在子宫内死亡（p.c.），这证明了 IMPA1 在早期胚胎发育中的重要性。有趣的是，怀孕母亲补充肌醇可以逆转胚胎致死率。在成年 IMPA1(-/-) 小鼠的大脑中，发现 IMPase 活性水平降低（海马中高达 65%）；然而，没有发现肌醇水平发生改变。 IMPA1(-/-) 小鼠的行为分析表明，在旷场测试和强迫游泳测试中运动活动均有所增加，并且对毛果芸香碱诱发的癫痫发作的敏感性也大大增加，后者支持了 IMPA1 代表锂的生理相关靶点的观点。总之，IMPA1(-/-) 小鼠代表了一种研究肌醇稳态的新模型，并表明 IMPA1 的基因失活可以模拟锂的某些作用。
Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene (IMPA1(-/-)) to study the in vivo physiological functions of IMPA1, in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPA1(-/-) mice died in utero between days 9.5 and 10.5 post coitum (p. c.) demonstrating the importance of IMPA1 in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPA1(-/-) mice, IMPase activity levels were found to be reduced ( up to 65% in hippocampus); however, inositol levels were not found to be altered. Behavioral analysis of the IMPA1(-/-) mice indicated an increased motor activity in both the open-field test and the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures, the latter supporting the idea that IMPA1 represents a physiologically relevant target for lithium. In conclusion the IMPA1(-/-) mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPA1 can mimic some actions of lithium.