Microglial circadian clock regulation of microglial structural complexity, dendritic spine density and inflammatory response
Microglial circadian clock regulation of microglial structural complexity, dendritic spine density and inflammatory response
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DOI：
10.1016/j.neuint.2020.104905
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发表时间：
2021-01-01
影响因子：
4.2
通讯作者：
Hayashi, Yoshinori
中科院分区：
文献类型：
--
作者：
Nakanishi, Hiroshi;Ni, Junjun;Hayashi, Yoshinori
皮质小胶质细胞在睡眠期间表现出分枝形状，而它们在清醒期间具有超分枝形状，其特征在于它们具有增加的分支点的较长突起。小胶质细胞分子昼夜节律钟调节脑中组织蛋白酶S（CatS）和P2 Y（12）受体的表达，在Zeitgeber时间14（黑暗期开始后2小时）达到峰值。我们推测，这两个小胶质细胞特异性分子有助于昼夜变化的小胶质细胞的形状和神经元的活动在大脑皮层。在清醒状态下，皮质小胶质细胞分泌的CatS可能参与P2 Y（12）受体依赖的过程延伸。分泌的CatS随后降解神经元周围的网络，启动向下缩放的棘密度和突触强度的皮层神经元对睡眠的开始。在睡眠期间，皮层神经元的棘密度和突触强度的降低可以改善信噪比，这将有利于记忆巩固，或者允许在随后的清醒期间发生新的学习。此外，CatS的破坏诱导小鼠的睡眠障碍和受损的社会互动。此外，小胶质细胞生物钟系统的破坏也可能在阿尔茨海默病的早期发病机制中发挥作用。低聚淀粉样蛋白β引起的皮质小胶质细胞BMAL 1表达减少可能通过ROR α的减少而诱导炎性表型的增加，进而导致I κ B α的减少和NF-κ B活化的增强。这些观察结果表明，小胶质细胞生物钟系统的破坏有助于睡眠障碍、社会互动受损和认知障碍的发病机制。因此，对小胶质细胞昼夜节律分子钟的日益了解可能有助于开发针对神经精神和神经退行性疾病的新型药物干预。
Cortical microglia exhibit a ramified shape during sleep, while they have a hyper-ramified shape during wakefulness, which is characterized by their longer processes with increased branching points. The microglial molecular circadian clock regulates expressions of both cathepsin S (CatS) and P2Y(12) receptors in the brain with a peak at zeitgeber time 14 (2 h after beginning of the dark phase). We postulated that these two microgliaspecific molecules contribute to diurnal alterations of microglial shapes and neuronal activities in the cerebral cortex. During wakefulness, CatS secreted from cortical microglia may be involved in P2Y(12) receptor-dependent process extension. Secreted CatS subsequently degrades the perineuronal nets, initiating the downscaling of both spine density and synaptic strength of cortical neurons toward the beginning of sleep. The downscaling of both spine density and synaptic strength of cortical neurons during sleep could improve signal-to-noise, which would benefit memory consolidation, or allow for new learning to occur during subsequent waking. Furthermore, disruption of CatS induces the sleep disturbance and impaired social interaction in mice. Moreover, the microglial clock system disruption may also play a role in the early pathogenesis of Alzheimer's disease. The reduced expression of BMAL1 in cortical microglia caused by oligomeric amyloid beta may induce the increased presence of inflammatory phenotype through a reduction in ROR alpha, which in turn reduced I kappa B alpha and enhanced NF-kappa B activation.These observations suggest that the microglial clock system disruption contribute to pathogeneses of sleep disturbance, impaired social interaction and cognitive impairment. Therefore, the growing understanding of the microglial circadian molecular clock might aid in the development of novel pharmacological interventions against both neuropsychiatric and neurodegenerative disorders.