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Published on: December 4, 2012
Phagocytic elimination of synapses by microglia during sleep
Mohammed E Choudhury1, Kazuya Miyanishi1, Haruna Takeda1
1Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
Abstract:
Synaptic strength reduces during sleep, but the underlying mechanisms of this process are unclear. This study showed reduction of synaptic proteins in rat prefrontal cortex (PFC) at AM7 or Zeitgeber Time (ZT0), when the light phase or sleeping period for rats started. At this time point, microglia were weakly activated, displaying larger and more granular somata with increased CD11b expression compared with those at ZT12, as revealed by flow cytometry. Expression of opsonins, such as complements or MFG-E8, matrix metalloproteinases, and microglial markers at ZT0 were increased compared with that at ZT12. Microglia at ZT0 phagocytosed synapses, as revealed by immunohistochemical staining. Immunoblotting detected more synapsin I in the isolated microglia at ZT0 than at ZT12. Complement C3- or MFG-E8-bound synapses were the most abundant at ZT0, some of which were phagocytosed by microglia. Systemic administration of synthetic glucocorticoid dexamethasone reduced microglial size, granularity and CD11b expression at ZT0, resembling microglia at ZT12, and increased synaptic proteins and decreased the sleeping period. Noradrenaline (NA) suppressed glutamate-induced phagocytosis in primary cultured microglia. Systemic administration of the brain monoamine-depleting agent reserpine decreased NA content and synapsin I expression in PFC, and increased expression of microglia markers, C3 and MFG-E8, while increasing the sleeping period. A NA precursor l-threo-dihydroxyphenylserine abolished the reserpine-induced changes. These results suggest that microglia may eliminate presumably weak synapses during every sleep phase. The circadian changes in concentrations of circulating glucocorticoids and brain NA might be correlated with the circadian changes of microglial phenotypes and synaptic strength.
Insights
Microglia eliminate weak synapses during sleep, a process influenced by circadian rhythms. Glucocorticoids and noradrenaline levels impact microglial activity and synaptic strength.
Area of Science:
- Neuroscience
- Cell Biology
- Sleep Research
Background:
- Synaptic strength reduction during sleep is a known phenomenon, but its underlying mechanisms remain largely unknown.
- Understanding how synapses are pruned during sleep is crucial for comprehending memory consolidation and brain plasticity.
Purpose of the Study:
- To investigate the role of microglia in synaptic elimination during the sleep phase in rats.
- To explore the influence of circadian rhythms, glucocorticoids, and noradrenaline on microglial activity and synaptic pruning.
Main Methods:
- Analysis of synaptic proteins and microglial markers in rat prefrontal cortex (PFC) at different Zeitgeber Times (ZT0 and ZT12) using flow cytometry and immunohistochemistry.
- Investigation of the effects of dexamethasone and reserpine administration on microglial phenotype, synaptic protein levels, and sleep duration.
- In vitro studies using primary cultured microglia to assess the impact of noradrenaline on synapse phagocytosis.
Main Results:
- Microglia exhibited increased activation, phagocytosis of synapses, and expression of opsonins and matrix metalloproteinases at ZT0 (start of the sleep phase).
- Dexamethasone treatment reduced microglial activation and increased synaptic proteins, while reserpine decreased noradrenaline, increased microglial markers, and prolonged sleep.
- Noradrenaline was found to suppress microglial phagocytosis of synapses.
Conclusions:
- Microglia actively eliminate weak synapses during sleep, contributing to the reduction in synaptic strength.
- Circadian fluctuations in glucocorticoids and noradrenaline levels are correlated with changes in microglial phenotype and synaptic strength.
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