The intrinsic microglial molecular clock controls synaptic strength via the circadian expression of cathepsin S.
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.
Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Yoshinori
Y
Hayashi
Satoru
S
Koyanagi
Naoki
N
Kusunose
Ryo
R
Okada
Zhou
Z
Wu
Hidetoshi
H
Tozaki-Saitoh
Kiyoharu
K
Ukai
Shinichi
S
Kohsaka
Kazuhide
K
Inoue
Shigehiro
S
Ohdo
Hiroshi
H
Nakanishi
D000818:Animals; D001683:Biological Clocks / Q000235:genetics; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002403:Cathepsins / Q000172:deficiency / Q000378:metabolism*; D002940:Circadian Rhythm / Q000235:genetics; D049229:Dendritic Spines / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D017628:Microglia / Q000378:metabolism*; D009043:Motor Activity; D059748:Proteolysis; D011994:Recombinant Proteins / Q000378:metabolism; D012890:Sleep; D013569:Synapses / Q000378:metabolism*
D011994:Recombinant Proteins; D056926:CLOCK Proteins; D002403:Cathepsins; C028217:cathepsin S