Angliker Nico, Burri Michael, Zaichuk Mariana, Fritschy Jean-Marc, Rüegg Markus A
Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056, Basel, Switzerland.
Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.
Eur J Neurosci. 2015 Oct;42(8):2595-612. doi: 10.1111/ejn.13051. Epub 2015 Sep 18.
The mammalian target of rapamycin (mTOR) is a key regulator of cellular growth which associates with other proteins to form two multi-protein complexes called mTORC1 and mTORC2. Dysregulation of mTORC1 signalling in brain is implicated in neuropathological conditions such as autism spectrum or neurodegenerative disorders. Accordingly, allosteric mTOR inhibitors are currently in clinical trials for the treatment of such disorders. Here, we ablated either mTORC1 or mTORC2 conditionally in Purkinje cells of the mouse cerebellum to dissect their role in the development, function and survival of these neurons. We find that the two mouse models largely differ from each other by phenotype and cellular responses. Inactivation of mTORC2, but not of mTORC1, led to motor coordination deficits at an early age. This phenotype correlated with developmental deficits in climbing fibre elimination and impaired dendritic self-avoidance in mTORC2-deficient Purkinje cells. In contrast, inactivation of mTORC1, but not of mTORC2, affected social interest of the mice and caused a progressive loss of Purkinje cells due to apoptosis. This cell loss was paralleled by age-dependent motor deficits. Comparison of mTORC1-deficient Purkinje cells with those deficient for the mTORC1 inhibitor TSC1 revealed a striking overlap in Purkinje cell degeneration and death, which included neurofilamentopathy and reactive gliosis. Altogether, our study reveals distinct roles of mTORC1 and mTORC2 in Purkinje cells for mouse behaviour and the survival of neurons. Our study also highlights a convergence between the phenotypes of Purkinje cells lacking mTORC1 activity and those expressing constitutively active mTORC1 due to TSC1 deficiency.
雷帕霉素的哺乳动物靶点（mTOR）是细胞生长的关键调节因子，它与其他蛋白质结合形成两种多蛋白复合物，即mTORC1和mTORC2。大脑中mTORC1信号失调与神经病理状况有关，如自闭症谱系障碍或神经退行性疾病。因此，变构mTOR抑制剂目前正处于治疗此类疾病的临床试验阶段。在此，我们有条件地在小鼠小脑的浦肯野细胞中消融mTORC1或mTORC2，以剖析它们在这些神经元的发育、功能和存活中的作用。我们发现，这两种小鼠模型在表型和细胞反应上有很大差异。mTORC2而非mTORC1的失活导致幼年时运动协调缺陷。这种表型与mTORC2缺陷的浦肯野细胞中攀缘纤维消除的发育缺陷和树突自我回避受损相关。相反，mTORC1而非mTORC2的失活影响了小鼠的社交兴趣，并由于细胞凋亡导致浦肯野细胞逐渐丧失。这种细胞丧失与年龄相关的运动缺陷平行。将mTORC1缺陷的浦肯野细胞与mTORC1抑制剂TSC1缺陷的细胞进行比较，发现浦肯野细胞变性和死亡存在显著重叠，包括神经丝病和反应性胶质增生。总之，我们的研究揭示了mTORC1和mTORC2在浦肯野细胞中对小鼠行为和神经元存活的不同作用。我们的研究还强调了缺乏mTORC1活性的浦肯野细胞与因TSC1缺陷而组成型激活mTORC1的浦肯野细胞在表型上的趋同。
