Neurological Disorders

Diurnal Spatial Rearrangement of Microglial Processes through the Rhythmic Expression of P2Y12 Receptors

Abstract

Yoshinori Hayashi, Satoru Koyanagi, Naoki Kusunose, Fumiko Takayama, Ryo Okada, Zhou Wu, Shigehiro Ohdo and Hiroshi Nakanishi

Microglia plays important roles in synaptic reorganization during the postnatal developmental stage. Moreover, microglia continuously surveys the functional state of the synapse and change to improve the function. This phenomenon was attributed to the fine process of extension and retraction. However, the mechanism underlying the dynamics of microglial movement and function is still unclear. We herein report that cortical microglia exhibit clock gene-regulated diurnal morphological changes. Cortical microglia extended their processes during the dark phase and retracted them during the light phase. These diurnal changes were also observed in cortical microglia from animals housed under constant darkness, but not in cortical microglia from clock-mutant mice. The mean contact ratio of the microglia-synapse interactions was significantly larger during the dark phase than the light phase. These diurnal changes in microglial morphology and microglia-synaptic interactions were significantly inhibited by the systemic administration of clopidogrel, a P2Y12 receptor (P2Y12R) blocker. We further observed diurnal variation in the P2Y12R expression in cortical microglia. The reporter analyses further revealed that P2Y12R was regulated by a negative feedback loop of the clock system. These observations suggest that the microglial clock system drives the diurnal morphological changes of microglia and microglia-synapse interactions by controlling the P2Y12R expression.