Glial Control of Synapse Number in Healthy and Diseased Brain

Lee, Eunbeol; Chung, Won‐Suk

doi:10.3389/fncel.2019.00042

Cited by 81 publications

(70 citation statements)

References 94 publications

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“…Expression of mRNA for MER receptor tyrosine kinase (MerTK), another eat‐me signal‐related protein, the chemokine receptor CX3CR1, and IRF1 were decreased at ZT12. CX3CR1 is responsible for synapse elimination (Lee & Chung, ; Paolicelli et al, ). Circadian expressional changes of mRNA were investigated every 4 hr (Figure c), demonstrating that the maximum expression of mRNA for MMPs, F4/80, a macrophage/activated microglia specific protein (Sun et al, ; Waddell et al, ), MFG‐E8, complements was observed at ZT0.…”

Section: Resultsmentioning

confidence: 99%

Phagocytic elimination of synapses by microglia during sleep

Choudhury

Miyanishi

Tamano

et al. 2019

Glia

108

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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.

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Section: Resultsmentioning

confidence: 99%

Phagocytic elimination of synapses by microglia during sleep

Choudhury

Miyanishi

Tamano

et al. 2019

Glia

108

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“…It has been shown that an increase in activated microglia leads to synaptic damage 45,46 , further leading to dysfunctional synaptic transmission in neurodegenerative diseases, measured by a significant loss of the preand post-synaptic proteins in the inflammatory state. Our results support this finding by estimating the levels of synaptic proteins (synaptophysin, PSD95) in the cerebellum of wild type and GFAP-IL6 mice (both normal-fed and LC-fed).…”

Section: Discussionmentioning

confidence: 99%

Effects of a solid lipid curcumin particle formulation on chronic activation of microglia and astroglia in the GFAP-IL6 mouse model

Ullah

Asgarov

Venigalla

et al. 2020

Sci Rep

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Chronic glial activation is characterized by increased numbers of activated glial cells, secreting free radicals and cytotoxic cytokines, subsequently causing neuronal damage. In order to investigate the anti-inflammatory activity of Longvida ® Optimised Curcumin (LC), we fed 500 ppm of LC to 2-monthold wild type and GFAP-IL6 mice for 6 months. LC feeding led to a significant reduction in the number of Iba-1 + microglia by 26% in the hippocampus and by 48% in the cerebellum, GFAP + astrocytes by 30%, and TSPO + cells by 24% in the hippocampus and by 31% in the cerebellum of the GFAP-IL6 mice. The morphology of the cells was assessed and LC significantly decreased the dendritic length of microglia and the convex area, convex perimeter, dendritic length, nodes and number of processes of astrocytes in the hippocampus while decreasing the soma area and perimeter in the cerebellum, in LC-fed GFAP-IL6 mice. In addition, LC feeding increased pre-and postsynaptic protein levels and improved balance measured by Rotarod. Together, these data suggest that LC is able to attenuate the inflammatory pathology and ameliorate neurodegeneration and motor deficits in GFAP-IL6 mice. For patients with neuro-inflammatory disorders, LC might potentially reverse the detrimental effects of chronic glial activation.In a healthy brain, microglia and astrocytes play a key role in the normal function of the central nervous system (CNS). The inflammatory response is mediated by the activated microglia, which is considered as the hallmark of neuroinflammation. The chronic activation of microglia leads to neuronal damage through the release of various cytotoxic molecules such as cytokines, reactive oxygen intermediates, and proteinases 1 . Microglia are involved in neural development including through phagocytosis of apoptotic cells. They also influence the function of neurons and their progenitor cells 2 . Astrocytes regulate synaptic transmission, for example through re-uptake of neurontransmitters such as glutamate, and support neurons with metabolic substrates such as gluthathione and lactate 3 .Chronic microglial activation, or neuroinflammation, has been described in many neurodegenerative diseases including chronic traumatic encephalopathy, amyotrophic lateral sclerosis, Parkinson's (PD) and Alzheimer's disease (AD) 4 . For sporadic AD, surmounting histological evidence points to chronic microglial activation as a part of the disease process 1,5 . Chronic microglial activation describes long lasting, CNS-specific, aberrant glial responses that do not reproduce the classic characteristics of inflammation although they do contribute to neurodegeneration 6 . To further support the role of neuroinflammation in AD, genome-wide association studies have identified a variety of inflammation-relevant genes that are associated with AD including clusterin (CLU), complement receptor 1 (CR1) and triggering receptor expressed on myeloid cells 2 (TREM2) 7 . The role of the microglial receptor TREM2 is to activate phagocytosis or microglial survival, an...

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“…In our study, we found a slight reduction in the number of Iba1-positive cells across the neocortex of Fmr1 KO mutants, further justifying the absence of microglial activation. It is likely that the reduction in microglia leads to less synapse elimination mediated by the complement pathway [68], and other mediators such as IL-33 and CX3CR1s [69].…”

Section: Discussionmentioning

confidence: 99%

Altered cortical Cytoarchitecture in the Fmr1 knockout mouse

Lee

Lai

et al. 2019

Mol Brain

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Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by silencing of the FMR1 gene and subsequent loss of its protein product, fragile X retardation protein (FMRP). One of the most robust neuropathological findings in post-mortem human FXS and Fmr1 KO mice is the abnormal increase in dendritic spine densities, with the majority of spines showing an elongated immature morphology. However, the exact mechanisms of how FMRP can regulate dendritic spine development are still unclear. Abnormal dendritic spines can result from disturbances of multiple factors during neurodevelopment, such as alterations in neuron numbers, position and glial cells. In this study, we undertook a comprehensive histological analysis of the cerebral cortex in Fmr1 KO mice. They displayed significantly fewer neuron and PV-interneuron numbers, along with altered cortical lamination patterns. In terms of glial cells, Fmr1 KO mice exhibited an increase in Olig2-oligodendrocytes, which corresponded to the abnormally higher myelin expression in the corpus callosum. Iba1-microglia were significantly reduced but GFAP-astrocyte numbers and intensity were elevated. Using primary astrocytes derived from KO mice, we further demonstrated the presence of astrogliosis characterized by an increase in GFAP expression and astrocyte hypertrophy. Our findings provide important information on the cortical architecture of Fmr1 KO mice, and insights towards possible mechanisms associated with FXS.

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Glial Control of Synapse Number in Healthy and Diseased Brain

Cited by 81 publications

References 94 publications

Phagocytic elimination of synapses by microglia during sleep

Phagocytic elimination of synapses by microglia during sleep

Effects of a solid lipid curcumin particle formulation on chronic activation of microglia and astroglia in the GFAP-IL6 mouse model

Altered cortical Cytoarchitecture in the Fmr1 knockout mouse

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