Requirement of AQP4 for Antidepressive Efficiency of Fluoxetine: Implication in Adult Hippocampal Neurogenesis
Requirement of AQP4 for Antidepressive Efficiency of Fluoxetine: Implication in Adult Hippocampal Neurogenesis
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AQP4 对氟西汀抗抑郁功效的要求：对成人海马神经发生的影响
DOI：
10.1038/npp.2008.185
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发表时间：
2009-04-01
影响因子：
7.6
通讯作者：
Hu, Gang
中科院分区：
文献类型：
--
作者：
Kong, Hui;Sha, Luo-lin;Hu, Gang
水通道蛋白-4（AQP 4）是维持中枢神经系统水平衡的关键分子，在成体神经干细胞（ANSC）和星形胶质细胞中表达。神经干细胞在整个成年期产生新的海马神经元，神经发生的缺陷可能使个体易于抑郁。然而，AQP 4在成年海马神经发生和慢性轻度应激（CMS）诱导的抑郁症中的作用仍然未知。我们在此报告，AQP 4基因敲除破坏了氟西汀（10 mg/kg/d ip）治疗4周诱导的成年小鼠海马神经发生的增强以及基础条件和CMS诱发的抑郁状态下的行为改善。同时，AQP 4基因敲除可消除氟西汀诱导的海马环腺苷酸反应元件结合蛋白（CREB）磷酸化增强。CMS程序抑制AQP 4 +/+和AQP 4 −/−小鼠中海马蛋白激酶A（PKA）活性、细胞外信号调节激酶（ERK 1/2）和钙/钙调蛋白依赖性蛋白激酶IV（CaMKIV）磷酸化。氟西汀治疗可以逆转CMS诱导的PKA活性和ERK 1/2磷酸化的抑制。然而，氟西汀在AQP 4 +/+小鼠中恢复了CMS诱导的海马CaMKIV磷酸化抑制，但在AQP 4 −/−小鼠中失败。值得注意的是，CMS程序显着增加海马AQP 4表达，这是由氟西汀治疗4周逆转。进一步的研究表明，AQP 4基因敲除可抑制体外培养的ANSC的增殖，并消除氟西汀的促增殖作用。总的来说，这些研究结果表明，AQP 4是通过调节成年海马神经发生的氟西汀的抗抑郁作用所必需的。
Aquaporin-4 (AQP4), a key molecule for maintaining water homeostasis in the central nervous system, is expressed in adult neural stem cells (ANSCs) as well as astrocytes. Neural stem cells give rise to new hippocampal neurons throughout adulthood, and defects in neurogenesis may predispose an individual to depression. Nevertheless, the role of AQP4 in adult hippocampal neurogenesis and chronic mild stress (CMS)-induced depression remains unknown. We herein report that AQP4 knockout disrupted 4-week fluoxetine (10 mg/kg per day ip) treatment-induced enhancement of adult mouse hippocampal neurogenesis as well as behavioral improvement under both basal condition and CMS-evoked depressive state. Meanwhile, AQP4 knockout abolished fluoxetine-induced enhancement of hippocampal cyclic AMP-responsive element binding protein (CREB) phosphorylation. The CMS procedure inhibited hippocampal protein kinase A (PKA) activity, extracellular signal-regulated kinases (ERK1/2), and calcium/calmodulin-dependent protein kinase IV (CaMKIV) phosphorylation in AQP4+/+ and AQP4−/− mice. Fluoxetine treatment could reverse CMS-induced inhibition of PKA activity and ERK1/2 phosphorylation in both genotypes. However, fluoxetine restored CMS-induced inhibition of hippocampal CaMKIV phosphorylation in AQP4+/+ mice but failed in AQP4−/− mice. Notably, CMS procedure significantly increased the hippocampal AQP4 expression, which was reversed by 4-week fluoxetine treatment. Further investigation showed AQP4 knockout inhibited the proliferation of cultured ANSCs and eliminated the pro-proliferative effect of fluoxetine in vitro. Collectively, these findings suggest that AQP4 is required for the antidepressive action of fluoxetine via regulating adult hippocampal neurogenesis.