Age-dependent Alteration in Mitochondrial Dynamics and Autophagy in Hippocampal Neuron of Cannabinoid CB1 Receptor-deficient Mice
Age-dependent Alteration in Mitochondrial Dynamics and Autophagy in Hippocampal Neuron of Cannabinoid CB1 Receptor-deficient Mice
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DOI：
10.1016/j.brainresbull.2020.03.014
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发表时间：
2020-07-01
影响因子：
3.8
通讯作者：
Asahi, Toru
中科院分区：
文献类型：
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作者：
Kataoka, Kosuke;Bilkei-Gorzo, Andras;Asahi, Toru
内源性大麻素系统的活性有助于对衰老的稳态防御，因此可以抵消大脑衰老的进展。大麻素1型（CB 1）受体活性随着大脑的衰老而下降，这会损害神经网络的完整性和认知功能。然而，联系CB 1活性和记忆衰退的潜在机制仍然未知。线粒体活性深刻地影响神经元功能，并且年龄依赖性线粒体活性变化是脑老化的已知标志之一。由于CB 1受体在线粒体上表达并可能调节海马神经元的能量代谢，因此我们假设CB 1受体可能影响海马神经元的线粒体。在这里，我们发现CB 1受体显着影响线粒体自噬（mitophagy）和形态的年龄依赖性方式。与野生型对照组相比，成年CB 1缺陷小鼠（CB 1-KO）中丝氨酸65-磷酸化泛素（线粒体自噬的关键标志物）减少，特别是在CA 1锥体细胞层中。透射电子显微镜（TEM）分析显示，减少线粒体吞噬样事件在成年CB 1-KO海马。TEM分析还表明，成年CB 1-KO小鼠的线粒体形态发生了改变，表现为海马神经元中细长线粒体的增加。扫描电子显微镜后线粒体形态的3D重建还显示了互连线粒体的密度增加。总之，这些发现表明，CB 1-KO小鼠中CB 1信号传导的减少导致衰老期间海马神经元线粒体自噬减少和线粒体形态异常。这些线粒体变化可能是由于线粒体质量控制系统的损伤，该系统将年龄相关的CB 1活性下降和记忆受损联系起来。
Endocannabinoid system activity contributes to the homeostatic defense against aging and thus may counteract the progression of brain aging. The cannabinoid type 1 (CB1) receptor activity declines with aging in the brain, which impairs neuronal network integrity and cognitive functions. However, the underlying mechanisms that link CB1 activity and memory decline remain unknown. Mitochondrial activity profoundly influences neuronal function, and age-dependent mitochondrial activity change is one of the known hallmarks of brain aging. As CB1 receptor is expressed on mitochondria and may regulate neuronal energy metabolism in hippocampus, we hypothesized that CB1 receptors might influence mitochondria in hippocampal neurons. Here, we found that CB1 receptor significantly affected mitochondrial autophagy (mitophagy) and morphology in an age-dependent manner. Serine 65-phosphorylated ubiquitin, a key marker for mitophagy, was reduced in adult CB1-deficient mice (CB1-KO) compared to those in wild type controls, particularly in CA1 pyramidal cell layer. Transmission electron microscopy (TEM) analysis showed reduced mitophagy-like events in hippocampus of adult CB1-KO. TEM analysis also showed that mitochondrial morphology in adult CB1-KO mice was altered shown by an increase in thin and elongated mitochondria in hippocampal neurons. 3D reconstruction of mitochondrial morphology after scanning electron microscopy additionally revealed an enhanced density of interconnected mitochondria. Altogether, these findings suggest that reduced CB1 signaling in CB1-KO mice leads to reduced mitophagy and abnormal mitochondrial morphology in hippocampal neurons during aging. These mitochondrial changes might be due to the impairments in mitochondrial quality control system, which links age-related decline in CB1 activity and impaired memory.