Viral expression of constitutively active AKT3 induces CST axonal sprouting and regeneration, but also promotes seizures
Viral expression of constitutively active AKT3 induces CST axonal sprouting and regeneration, but also promotes seizures
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DOI：
10.1016/j.expneurol.2021.113961
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发表时间：
2022-01-05
影响因子：
5.3
通讯作者：
Smith, George M.
中科院分区：
文献类型：
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作者：
Campion, Thomas J.;Sheikh, Imran S.;Smith, George M.
在啮齿动物模型中，损伤后增加神经元的内在生长潜力已多次被证明可以促进一定程度的轴突再生。研究最多的途径之一涉及 PI3K/AKT/mTOR 途径的激活，主要通过降低 PTEN（PI3K 的负调节因子）的水平来实现。同样，信号转导器和转录激活剂 3 (STAT3) 的激活先前已被证明可以促进受损神经系统内的轴突再生和发芽。在这里，我们检查了皮质表达组成型活性 (ca) Akt3 和 STAT3 后皮质脊髓束 (CST) 的再生，无论是单独还是组合。 caAkt3 的过表达诱导损伤部位后的 CST 轴突再生，与 caSTAT3 的过表达无关。与对照组相比，STAT3 表现出轴突萌芽得到改善，并且与 Akt3 联合使用时有助于协同改善效果，但作为个体疗法未能促进轴突再生。尽管表现出令人印象深刻的轴突再生，但表达 Akt3 的动物未能表现出任何功能改善，并且随着时间的推移而恶化。在此期间，我们观察到行为性癫痫发作呈剂量依赖性进行性 Akt3 增加。组织学显示单侧皮质内核糖体 S6 蛋白磷酸化增加、神经元大小增加、小胶质细胞激活和半球增大（半巨脑畸形）。
Increasing the intrinsic growth potential of neurons after injury has repeatedly been shown to promote some level of axonal regeneration in rodent models. One of the most studied pathways involves the activation of the PI3K/AKT/mTOR pathways, primarily by reducing the levels of PTEN, a negative regulator of PI3K. Likewise, activation of signal transducer and activator of transcription 3 (STAT3) has previously been shown to boost axonal regeneration and sprouting within the injured nervous system. Here, we examined the regeneration of the corticospinal tract (CST) after cortical expression of constitutively active (ca) Akt3 and STAT3, both separately and in combination. Overexpression of caAkt3 induced regeneration of CST axons past the injury site independent of caSTAT3 overexpression. STAT3 demonstrated improved axon sprouting compared to controls and contributed to a synergistic improvement in effects when combined with Akt3 but failed to promote axonal regeneration as an individual therapy. Despite showing impressive axonal regeneration, animals expressing Akt3 failed to show any functional improvement and deteriorated with time. During this period, we observed progressive Akt3 dose-dependent increase in behavioral seizures. Histology revealed increased phosphorylation of ribosomal S6 protein within the unilateral cortex, increased neuronal size, microglia activation and hemispheric enlargement (hemimegalencephaly).