Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain.
Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain.
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DOI：
10.3389/fnmol.2018.00409
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发表时间：
2018
影响因子：
4.8
通讯作者：
Yoshii A
中科院分区：
文献类型：
--
作者：
Cox RL;Calderon de Anda F;Mangoubi T;Yoshii A
结节性硬化症（TSC）是一种常染色体显性神经遗传疾病，影响大脑和其他重要器官。神经系统症状包括癫痫、智力残疾和自闭症。TSC是由TSC1或TSC2基因的功能缺失突变引起的。这些基因产物形成蛋白质复合物，通常抑制哺乳动物雷帕霉素靶蛋白（mTOR）活性。mTOR抑制剂已被用于治疗室管膜下胶质瘤（SEGA），这是一种具有TSC特征的脑肿瘤。然而，TSC的神经病理学也涉及皮质回路形成失调，包括神经元迁移、轴突分化和突触形成。目前尚不清楚mTOR信号抑制剂在多大程度上纠正了治疗前已经形成的神经元形态的改变。在这里，我们讨论了雷帕霉素治疗对神经元迁移和树突形成的影响。利用子宫电穿孔技术，我们在胎儿时期抑制了一部分神经祖细胞中Tsc1的表达。在胚胎脑切片中，我们发现更多的tsc1抑制细胞留在心室周围区，雷帕霉素治疗促进了神经元的迁移。出生后，tsc1抑制的锥体神经元显示出更复杂的基底树突分支和更高的脊柱密度(P) 28。在P1和P13之间，每隔一天给雷帕霉素使异常的树木生长正常化，而在P15和P27之间则没有。相比之下，雷帕霉素治疗在P15和P27之间改善了异常脊柱成熟，而在P1和P13之间没有改善。我们的研究结果表明，纠正TSC结构异常的不同方面存在多个关键窗口，其反应取决于神经元回路形成的阶段。这些数据为寻找治疗TSC神经症状的额外治疗靶点提供了依据。
Tuberous sclerosis complex (TSC) is an autosomal dominant neurogenetic disorder affecting the brain and other vital organs. Neurological symptoms include epilepsy, intellectual disability, and autism. TSC is caused by a loss-of-function mutation in the TSC1 or TSC2 gene. These gene products form a protein complex and normally suppress mammalian target of rapamycin (mTOR) activity. mTOR inhibitors have been used to treat subependymal glioma (SEGA) that is a brain tumor characteristic of TSC. However, neuropathology of TSC also involves dysregulated cortical circuit formation including neuronal migration, axodendritic differentiation, and synapse formation. It is currently unknown to what extent mTOR signaling inhibitors correct an alteration in neuronal morphology that have already formed prior to the treatment. Here, we address the efficacy of rapamycin treatment on neuronal migration and dendrite formation. Using in utero electroporation, we suppressed Tsc1 expression in a fraction of neuronal progenitor cells during the fetal period. In embryonic brain slices, we found that more Tsc1-suppressed cells remained within the periventricular zone, and rapamycin treatment facilitated neuronal migration. Postnatally, Tsc1-suppressed pyramidal neurons showed more complex branching of basal dendrites and a higher spine density at postnatal day (P) 28. Aberrant arborization was normalized by rapamycin administration every other day between P1 and P13 but not P15 and P27. In contrast, abnormal spine maturation improved by rapamycin treatment between P15 and P27 but not P1 and P13. Our results indicate that there are multiple critical windows for correcting different aspects of structural abnormalities in TSC, and the responses depend on the stage of neuronal circuit formation. These data warrant a search for an additional therapeutic target to treat neurological symptoms of TSC.
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影响因子：
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作者：
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