Pharmacological treatment with mirtazapine rescues cortical atrophy and respiratory deficits in MeCP2 null mice
Pharmacological treatment with mirtazapine rescues cortical atrophy and respiratory deficits in MeCP2 null mice
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DOI：
10.1038/srep19796
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发表时间：
2016-01-25
影响因子：
4.6
通讯作者：
Tongiorgi, Enrico
中科院分区：
文献类型：
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作者：
Bittolo, Tamara;Raminelli, Carlo Antonio;Tongiorgi, Enrico
Rett 综合征 (RTT) 中 MeCP2（甲基 CpG 结合蛋白 2）的缺失会导致脑重量减轻、皮质萎缩、树突状树枝化减少、行为异常、癫痫发作和心肺并发症。观察到的 RTT 中单胺神经递质减少表明抗抑郁药物是一种可能的治疗方法。我们从出生后第 28 天开始，用地昔帕明（已在 RTT 中进行过测试）或米氮平（一种副作用有限的抗抑郁药，已知可促进 GABA 释放）治疗 MeCP2 缺失小鼠两周。米氮平通过充分挽救锥体神经元树突状结构和棘密度，在恢复体感皮层厚度方面比地昔帕明更有效。从功能上讲，米氮平治疗使心率、呼吸频率、焦虑水平正常化，并消除了在 MeCP2 缺失小鼠中观察到的跳跃行为，从而改善了表型评分。米氮平的这些形态和功能影响伴随着皮层和脑干组织中记录的 GABA 能和谷氨酸能受体活性的重建。因此，米氮平可以代表雷特综合征的一种新的潜在药物治疗方法。
Loss of MeCP2 (Methyl CpG binding protein 2) in Rett syndrome (RTT) causes brain weight decrease, shrinkage of the cortex with reduced dendritic arborization, behavioral abnormalities, seizures and cardio-respiratory complications. The observed monoamine neurotransmitters reduction in RTT suggested antidepressants as a possible therapy. We treated MeCP2-null mice from postnatal -day 28 for two weeks with desipramine, already tested in RTT, or mirtazapine, an antidepressant with limited side-effects, known to promote GABA release. Mirtazapine was more effective than desipramine in restoring somatosensory cortex thickness by fully rescuing pyramidal neurons dendritic arborization and spine density. Functionally, mirtazapine treatment normalized heart rate, breath rate, anxiety levels, and eliminated the hopping behavior observed in MeCP2-null mice, leading to improved phenotypic score. These morphological and functional effects of mirtazapine were accompanied by reestablishment of the GABAergic and glutamatergic receptor activity recorded in cortex and brainstem tissues. Thus, mirtazapine can represent a new potential pharmacological treatment for the Rett syndrome.