Calcineurin (protein phosphatase 2B) is involved in the mechanisms of action of antidepressants
Calcineurin (protein phosphatase 2B) is involved in the mechanisms of action of antidepressants
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DOI：
10.1016/j.neuroscience.2006.11.030
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发表时间：
2007-02-23
期刊：
影响因子：
3.3
通讯作者：
Tzavara, E. T.
中科院分区：
文献类型：
--
作者：
Crozatier, C.;Farley, S.;Tzavara, E. T.
钙调神经磷酸酶 (PP2B) 是一种富含大脑的 Ca2+ 依赖性蛋白磷酸酶，参与调节突触可塑性和神经元功能的细胞内信号传导通路。钙调磷酸酶依赖性途径对于学习和记忆等复杂的大脑功能很重要。最近，有人认为它们在情绪信息的处理中发挥作用。本研究的目的是调查钙调神经磷酸酶是否可能参与抗抑郁药的作用。我们首先发现，对小鼠进行长期抗抑郁治疗会导致海马中钙调神经磷酸酶水平升高。然后，我们研究了海马钙调神经磷酸酶基因过度激活的小鼠（组成型激活的钙调神经磷酸酶转基因小鼠系#98，CN98 小鼠）对氟西汀的行为和分子反应。我们观察到CN98小鼠对悬尾试验中氟西汀和地昔帕明的行为效应更敏感。此外，生长因子脑源性神经营养因子和 AMPA 谷氨酸受体 GluR1 亚基 1 的基础表达在 CN98 小鼠的海马中发生改变，这两者在长期服用抗抑郁药物后都会发生改变。这些结果表明，钙依赖磷酸酶依赖性去磷酸化在抗抑郁药的作用机制中发挥着重要作用，为开发改进的抑郁症治疗方法提供了新的起点。 (c) 2006 年国际广播组织。由爱思唯尔有限公司出版。保留所有权利。
Calcineurin (PP2B) is a Ca2+-dependent protein phosphatase enriched in the brain that takes part in intracellular signaling pathways regulating synaptic plasticity and neuronal functions. Calcineurin-dependent pathways are important for complex brain functions such as learning and memory. More recently, they have been suggested to play a role in the processing of emotional information. The aim of this study was to investigate whether calcineurin may be involved in the effect of antidepressants. We first found that chronic antidepressant treatment in mice leads to an increase of calcineurin levels in the hippocampus. We then studied the behavioral and molecular responses to fluoxetine of mice with a genetic overactivation of calcineurin in the hippocampus (constitutively-activated calcineurin transgenic mouse line #98, CN98 mice). We observed that CN98 mice are more sensitive to the behavioral effect of fluoxetine and desipramine tested in the tail suspension test. Moreover, the basal expression of growth factor brain-derived neurotrophic factor and subunit 1 of AMPA glutamate receptor, GluR1, both of which are modified after chronic antidepressant administration, are altered in the hippocampus of CN98 mice. These results suggest that calcineurin-dependent dephosphorylation plays an important role in the mechanisms of action of antidepressants, providing a new starting point for developing improved therapeutic treatments for depression. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.