Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia
Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia
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DOI：
10.1242/dmm.002386
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发表时间：
2009-07-01
影响因子：
4.3
通讯作者：
D'Arcangelo, Gabriella
中科院分区：
文献类型：
--
作者：
Ljungberg, M. Cecilia;Sunnen, C. Nicole;D'Arcangelo, Gabriella
被称为皮质发育不良的大脑皮层畸形是大多数顽固性儿童癫痫的原因。除了结节性硬化症，大多数类型的皮质发育不良的分子基础是完全未知的。目前，还没有良好的动物模型可以概括该病的关键特征，如结构皮质异常和癫痫发作，阻碍了对皮质发育不良的理解和治疗的进展。在神经解剖学水平上，皮质异常可能包括椎板运动障碍和异常细胞类型的存在，如增大和定向错误的神经元和神经胶质细胞。最近在切除的人脑组织中的研究表明，PI3K(磷脂酰肌醇3-激酶)-Akt-mTOR(哺乳动物雷帕霉素靶标)信号通路的错误调节可能是该病中发育不良细胞过度生长的原因。在这里，我们将神经元亚集(NS)-Pten突变小鼠描述为皮质发育不良的动物模型。在这些小鼠中，通过使用Cre-loxP技术，编码PI3K途径抑制物的Pten基因在部分神经元中被选择性地破坏。我们的数据表明，这些突变小鼠，就像皮质发育不良患者一样，表现出皮质神经元增大，mTOR活性增加，脑电活动异常并伴有自发性癫痫发作。我们还证明，mTOR抑制剂雷帕霉素的短期治疗可以强烈抑制癫痫发作的严重程度和持续时间。这些发现支持这种药物可能被开发为治疗皮质发育不良和类似疾病患者的一种新的抗癫痫药物。
Malformations of the cerebral cortex known as cortical dysplasia account for the majority of cases of intractable childhood epilepsy. With the exception of the tuberous sclerosis complex, the molecular basis of most types of cortical dysplasia is completely unknown. Currently, there are no good animal models available that recapitulate key features of the disease, such as structural cortical abnormalities and seizures, hindering progress in understanding and treating cortical dysplasia. At the neuroanatomical level, cortical abnormalities may include dyslamination and the presence of abnormal cell types, such as enlarged and misoriented neurons and neuroglial cells. Recent studies in resected human brain tissue suggested that a misregulation of the PI3K (phosphoinositide 3-kinase)-Akt-mTOR (mammalian target of rapamycin) signaling pathway might be responsible for the excessive growth of dysplastic cells in this disease. Here, we characterize neuronal subset (NS)-Pten mutant mice as an animal model of cortical dysplasia. In these mice, the Pten gene, which encodes a suppressor of the PI3K pathway, was selectively disrupted in a subset of neurons by using Cre-loxP technology. Our data indicate that these mutant mice, like cortical dysplasia patients, exhibit enlarged cortical neurons with increased mTOR activity, and abnormal electroencephalographic activity with spontaneous seizures. We also demonstrate that a short-term treatment with the mTOR inhibitor rapamycin strongly suppresses the severity and the duration of the seizure activity. These findings support the possibility that this drug may be developed as a novel antiepileptic treatment for patients with cortical dysplasia and similar disorders.