Epac-mediated cAMP-signalling in the mouse model of Rett Syndrome
Epac-mediated cAMP-signalling in the mouse model of Rett Syndrome
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DOI：
10.1016/j.neuropharm.2011.01.002
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发表时间：
2011-05-01
影响因子：
4.7
通讯作者：
Kuegler, S.
中科院分区：
文献类型：
--
作者：
Mironov, S. L.;Skorova, E. Y.;Kuegler, S.
Rett综合征（RTT）是一种神经发育疾病，被认为是由突触发生和神经元回路缺陷引起的。cAMP是神经元生长、可塑性和再生的关键因子之一。我们检查了它的动态平衡在RTT出生后早期发育的呼吸网络的重要部分，前波青格复合体。通过epac1 - CAMP传感器在神经元中的靶向表达，我们量化了MeCP2-/y小鼠（已建立的RTT模型）的CAMP水平及其波动。突变体的静息cAMP水平低于野生型。腺苷酸环化酶去极化和刺激引起的cAMP瞬态也具有更小的振幅和更快的时间过程。用罗利普兰抑制磷酸二酯酶PDE4后，MeCP2 -/y小鼠的异常被消除。CAMP短暂升高引发的神经元突起伸长在野生型中明显更大。在抑制蛋白激酶A后观察到这种作用，并通过激活鸟嘌呤核苷酸交换因子模拟。Epac，与8-（4-氯苯基硫）-2'- o -甲基腺苷-3',5'-环单磷酸（8- pcpt）。激动剂增强了突变体preBotC神经元的破裂，并将其转化为野生型。8-pCPT的所有作用都不能被其非活性类似物复制，并被Epac信号抑制剂Brefeldin a消除。我们提出，MeCP2 -/y小鼠cAMP稳态紊乱可能导致Epac信号传导不足。伴随的呼吸回路发育缺陷可能是RTT患者呼吸活动不规则的原因。(C) 2011 Elsevier Ltd.版权所有。
Rett Syndrome (RTT) is a neurodevelopmental disease thought to be caused by deficits in synaptogenesis and neuronal circuitry. cAMP is one of the key factors for neuronal outgrowth, plasticity and regeneration. We examined its homeostasis in RTT during early postnatal development of the essential part of the respiratory network, pre-Botzinger complex. Using targeted expression of Epac1-camps sensor in neurons we quantified CAMP levels and their fluctuations in MeCP2-/y mice, an established model of RTT. Resting cAMP levels in the mutant were smaller than in the wild-type. cAMP transients elicited by depolarisation and stimulation of adenylate cyclase had also smaller amplitudes and faster time-courses. The anomalies in MeCP2 -/y mice were removed after inhibition of phosphodiesterase PDE4 with rolipram. Brief CAMP elevations triggered elongation of neuronal processes that was significantly bigger in the wild-type. The effects were observed after inhibition of protein kinase A and mimicked by activation of a guanine nucleotide exchange factor. Epac, with 8-(4-Chlorophenylthio)-2'-O-methyl-adenosine-3',5'-cyclic monophosphate (8-pCPT). The agonist reinforced bursting in preBotC neurons in the mutant and converted it to the wild-type. All actions of 8-pCPT were not reproduced by its non-active analogue and abolished by Epac signalling inhibitor Brefeldin A. We propose that disturbances in cAMP homeostasis in MeCP2 -/y mice can lead to inadequate Epac signalling. Concomitant defective development of respiratory circuits may be responsible for irregular breathing activity in RTT. (C) 2011 Elsevier Ltd. All rights reserved.