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Updated: May 7, 2026
Transmission Electron Microscopy as the Visualization Technique for Analysis of Circadian Synaptic Plasticity in the Mouse Barrel Cortex
Published on: August 19, 2025
The intrinsic microglial molecular clock controls synaptic strength via the circadian expression of cathepsin S
Yoshinori Hayashi1, Satoru Koyanagi, Naoki Kusunose
1Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Abstract:
Microglia are thought to play important roles in the maintenance of neuronal circuitry and the regulation of behavior. We found that the cortical microglia contain an intrinsic molecular clock and exhibit a circadian expression of cathepsin S (CatS), a microglia-specific lysosomal cysteine protease in the brain. The genetic deletion of CatS causes mice to exhibit hyperlocomotor activity and removes diurnal variations in the synaptic activity and spine density of the cortical neurons, which are significantly higher during the dark (waking) phase than the light (sleeping) phase. Furthermore, incubation with recombinant CatS significantly reduced the synaptic activity of the cortical neurons. These results suggest that CatS secreted by microglia during the dark-phase decreases the spine density of the cortical neurons by modifying the perisynaptic environment, leading to downscaling of the synaptic strength during the subsequent light-phase. Disruption of CatS therefore induces hyperlocomotor activity due to failure to downscale the synaptic strength.
Insights
Cortical microglia regulate brain activity via cathepsin S (CatS), a protease with circadian expression. Deleting CatS disrupts synaptic downscaling, causing hyperactivity in mice.
Area of Science:
- Neuroscience
- Cell Biology
- Chronobiology
Background:
- Microglia are crucial for neuronal circuit maintenance and behavioral regulation.
- Microglia possess intrinsic molecular clocks influencing brain function.
- Cathepsin S (CatS) is a microglia-specific lysosomal protease in the brain.
Purpose of the Study:
- To investigate the role of cathepsin S (CatS) in microglia-mediated synaptic plasticity and behavior.
- To elucidate the circadian regulation of CatS in cortical microglia.
- To determine the impact of CatS disruption on neuronal activity and mouse behavior.
Main Methods:
- Analysis of circadian gene expression in cortical microglia.
- Genetic deletion of CatS in mice.
- Measurement of synaptic activity and spine density in cortical neurons.
- In vitro incubation of cortical neurons with recombinant CatS.
Main Results:
- Cortical microglia exhibit circadian expression of cathepsin S (CatS).
- Genetic deletion of CatS led to hyperlocomotor activity in mice.
- Loss of CatS abolished diurnal variations in synaptic activity and spine density.
- Recombinant CatS reduced cortical neuronal synaptic activity in vitro.
Conclusions:
- Microglial CatS plays a key role in downscaling synaptic strength during the light (sleep) phase.
- CatS modifies the perisynaptic environment, reducing synaptic density and activity.
- Disruption of microglial CatS impairs synaptic homeostasis, leading to behavioral changes like hyperactivity.
