IGF1-Stimulated Posttraumatic Hippocampal Remodeling Is Not Dependent on mTOR.
IGF1-Stimulated Posttraumatic Hippocampal Remodeling Is Not Dependent on mTOR.
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DOI：
10.3389/fcell.2021.663456
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发表时间：
2021
影响因子：
5.5
通讯作者：
Saatman KE
中科院分区：
文献类型：
--
作者：
Littlejohn EL;DeSana AJ;Williams HC;Chapman RT;Joseph B;Juras JA;Saatman KE
成人海马神经发生在创伤性脑损伤（TBI）后受到急性刺激。然而，许多损伤后生成的海马神经元发育异常，并且长期存活的数量存在争议。在实验性TBI中，胰岛素样生长因子-1（IGF1）促进海马神经元分化，改善未成熟神经元树突状乔木形态，增加TBI后产生的神经元的长期存活，并改善认知功能。 IGF1 神经源性效应的一种潜在下游介质是哺乳动物雷帕霉素靶点 (mTOR)，它调节中枢神经系统的增殖以及轴突和树突的生长。过度的 mTOR 激活被认为会导致与创伤后癫痫相关的异常可塑性，从而刺激了 mTOR 抑制剂作为 TBI 治疗药物的临床前研究。 IGF1 的促神经发生作用在多大程度上依赖于 mTOR 活性的上调目前尚不清楚。使用磷酸化核糖体蛋白 S6（mTOR 激活的常用替代物）的免疫染色，我们发现受控皮质冲击 TBI 以时间、区域和损伤严重程度依赖性方式触发齿状回中的 mTOR 激活。在有条件过度表达 IGF1 的小鼠中，颗粒细胞层 (GCL) 和齿状门中的创伤后 mTOR 激活被放大。相比之下，齿状回分子层内 mTOR 信号传导的延迟星形细胞激活（与增殖密切相关）不受 IGF1 过表达的影响。为了确定 mTOR 激活对于 IGF1 介导的创伤后海马神经发生刺激是否是必要的，野生型和 IGF1 转基因小鼠从 TBI 后 3 天开始每天接受 mTOR 抑制剂雷帕霉素，随后用溴脱氧尿苷进行脉冲标记。与野生型小鼠相比，IGF1过表达小鼠表现出创伤后神经发生增加，在受伤后10天，创伤后产生的GCL神经元密度更高。 mTOR 的抑制并没有消除 IGF1 刺激的创伤后神经发生的增强。相反，雷帕霉素对 IGF1 转基因小鼠（而非 WT 小鼠）的治疗增加了损伤后 3 天时用 BrdU 标记的细胞数量，这些细胞存活至 10 天，并提高了创伤后分化为神经元的细胞的比例。由于延迟抑制 mTOR 可以维持甚至增强 IGF1 对海马神经发生的有益作用，因此联合治疗方法可能有望治疗 TBI。
Adult hippocampal neurogenesis is stimulated acutely following traumatic brain injury (TBI). However, many hippocampal neurons born after injury develop abnormally and the number that survive long-term is debated. In experimental TBI, insulin-like growth factor-1 (IGF1) promotes hippocampal neuronal differentiation, improves immature neuron dendritic arbor morphology, increases long-term survival of neurons born after TBI, and improves cognitive function. One potential downstream mediator of the neurogenic effects of IGF1 is mammalian target of rapamycin (mTOR), which regulates proliferation as well as axonal and dendritic growth in the CNS. Excessive mTOR activation is posited to contribute to aberrant plasticity related to posttraumatic epilepsy, spurring preclinical studies of mTOR inhibitors as therapeutics for TBI. The degree to which pro-neurogenic effects of IGF1 depend upon upregulation of mTOR activity is currently unknown. Using immunostaining for phosphorylated ribosomal protein S6, a commonly used surrogate for mTOR activation, we show that controlled cortical impact TBI triggers mTOR activation in the dentate gyrus in a time-, region-, and injury severity-dependent manner. Posttraumatic mTOR activation in the granule cell layer (GCL) and dentate hilus was amplified in mice with conditional overexpression of IGF1. In contrast, delayed astrocytic activation of mTOR signaling within the dentate gyrus molecular layer, closely associated with proliferation, was not affected by IGF1 overexpression. To determine whether mTOR activation is necessary for IGF1-mediated stimulation of posttraumatic hippocampal neurogenesis, wildtype and IGF1 transgenic mice received the mTOR inhibitor rapamycin daily beginning at 3 days after TBI, following pulse labeling with bromodeoxyuridine. Compared to wildtype mice, IGF1 overexpressing mice exhibited increased posttraumatic neurogenesis, with a higher density of posttrauma-born GCL neurons at 10 days after injury. Inhibition of mTOR did not abrogate IGF1-stimulated enhancement of posttraumatic neurogenesis. Rather, rapamycin treatment in IGF1 transgenic mice, but not in WT mice, increased numbers of cells labeled with BrdU at 3 days after injury that survived to 10 days, and enhanced the proportion of posttrauma-born cells that differentiated into neurons. Because beneficial effects of IGF1 on hippocampal neurogenesis were maintained or even enhanced with delayed inhibition of mTOR, combination therapy approaches may hold promise for TBI.
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3.5
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