Mecp2 deficiency disrupts norepinephrine and respiratory systems in mice
Mecp2 deficiency disrupts norepinephrine and respiratory systems in mice
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DOI：
10.1523/jneurosci.4373-05.2005
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发表时间：
2005-12-14
影响因子：
5.3
通讯作者：
Hilaire, G
中科院分区：
文献类型：
--
作者：
Viemari, JC;Roux, JC;Hilaire, G
Rett综合征是一种严重的X连锁神经系统疾病，其中大多数患者在甲基-CpG结合蛋白2（MECP 2）基因中具有突变，并且患有生物胺能缺陷和危及生命的呼吸障碍。我们使用体内体积描记法、体外电生理学、神经药理学、免疫组织化学和生物化学来表征MECP 2突变对野生型（wt）和Mecp 2缺陷型（Mecp 2-/y）小鼠呼吸的影响。出生时，Mecp 2-/y小鼠表现出正常的呼吸和正常数量的表达酪氨酸羟化酶的髓质神经元（TH神经元）。在近似1月龄时，大多数Mecp 2-/y小鼠表现出不同持续时间的呼吸周期;同时，它们的髓质含有数量显著减少的TH神经元和去甲肾上腺素（NE）含量，即使在表现出正常呼吸模式的Mecp 2-/y小鼠中也是如此。在1至2月龄之间，所有未麻醉的Mecp 2-/y小鼠均显示呼吸障碍，其恶化直至在类似于2月龄时致命的呼吸骤停。在其生命的最后一周，Mecp 2-/y小鼠具有缓慢且不稳定的呼吸模式，具有高度可变的周期和频繁的呼吸暂停。此外，他们的髓质TH神经元数量，NE含量和5-羟色胺（5-HT）含量急剧减少。在体外实验中，使用2和3周龄之间的小鼠的横向脑干切片显示，由孤立的呼吸网络产生的节奏是不规则的Mecp 2-/y小鼠，但可以稳定与外源性NE。我们假设Mecp 2-/y小鼠的呼吸障碍，可能是Rett患者，部分源于髓质呼吸网络的去甲肾上腺素能和肾上腺素能调节的缺乏。
Rett syndrome is a severe X-linked neurological disorder in which most patients have mutations in the methyl-CpG binding protein 2 (MECP2) gene and suffer from bioaminergic deficiencies and life-threatening breathing disturbances. We used in vivo plethysmography, in vitro electrophysiology, neuropharmacology, immunohistochemistry, and biochemistry to characterize the consequences of the MECP2 mutation on breathing in wild-type (wt) and Mecp2-deficient (Mecp2-/y) mice. At birth, Mecp2-/y mice showed normal breathing and a normal number of medullary neurons that express tyrosine hydroxylase (TH neurons). At similar to 1 month of age, most Mecp2-/y mice showed respiratory cycles of variable duration; meanwhile, their medulla contained a significantly reduced number of TH neurons and norepinephrine (NE) content, even in Mecp2-/y mice that showed a normal breathing pattern. Between 1 and 2 months of age, all unanesthetized Mecp2-/y mice showed breathing disturbances that worsened until fatal respiratory arrest at similar to 2 months of age. During their last week of life, Mecp2-/y mice had a slow and erratic breathing pattern with a highly variable cycle period and frequent apneas. In addition, their medulla had a drastically reduced number of TH neurons, NE content, and serotonin (5-HT) content. In vitro experiments using transverse brainstem slices of mice between 2 and 3 weeks of age revealed that the rhythm produced by the isolated respiratory network was irregular in Mecp2-/y mice but could be stabilized with exogenous NE. We hypothesize that breathing disturbances in Mecp2-/y mice, and probably Rett patients, originate in part from a deficiency in noradrenergic and serotonergic modulation of the medullary respiratory network.