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 P2Y₁₂ receptors in the brain with a peak at zeitgeber time 14 (2 h after beginning of the dark phase). We postulated that these two microglia-specific 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 P2Y₁₂ 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 β may induce the increased presence of inflammatory phenotype through a reduction in RORα, which in turn reduced IκBα and enhanced NF-κB 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.

皮层小胶质细胞在睡眠期间呈现分枝状，而在清醒时呈超分枝状，其特征是它们的过程更长，分支点增加。小胶质细胞分子生物钟调节大脑中组织蛋白酶 S (CatS) 和 P2Y ₁₂受体的表达，在 zeitgeber 时间 14（黑暗阶段开始后 2 小时）达到峰值。我们假设这两种小胶质细胞特异性分子有助于大脑皮层中小胶质细胞形状和神经元活动的昼夜变化。在清醒期间，皮层小胶质细胞分泌的 CatS 可能参与 P2Y ₁₂受体依赖性过程扩展。分泌的 CatS 随后会降解神经周围网，在睡眠开始前开始降低皮质神经元的脊密度和突触强度。睡眠期间皮质神经元的脊柱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，或者允许在随后的醒来期间进行新的学习。此外，CatS 的破坏会导致小鼠的睡眠障碍和社交互动受损。此外，小胶质细胞时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。由寡聚淀粉样蛋白 β 引起的皮质小胶质细胞中 BMAL1 的表达降低可能通过降低 RORα 来诱导炎症表型的增加，

这些观察结果表明，小胶质细胞时钟系统的破坏会导致睡眠障碍、社会交往受损和认知障碍的发病机制。因此，对小胶质细胞生物钟分子钟的日益了解可能有助于开发针对神经精神疾病和神经退行性疾病的新型药物干预措施。