Receptors, Ion Channels, and Signaling Mechanisms Underlying Microglial Dynamics

Madry, Christian; Attwell, David

doi:10.1074/jbc.r115.637157

Cited by 76 publications

(67 citation statements)

References 74 publications

(123 reference statements)

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“…Perhaps microglial mobility is more directly regulated by developmental changes in synaptic function, including changes in neurotransmitter or gliotransmitter signaling. Because purines have been shown to strongly regulate microglial motility and migration (Madry and Attwell 2015; Ohsawa and Kohsaka 2011) these molecules are good candidates for regulating developmental changes in microglial behavior. However, microglia in P2Y12 receptor KO mice retain basal motility (Haynes et al 2006), indicating that other signaling pathways must regulate these features of microglial behavior.…”

Section: Discussionmentioning

confidence: 99%

Developmental changes in microglial mobilization are independent of apoptosis in the neonatal mouse hippocampus

Eyo

Miner

Weiner

et al. 2016

Brain, Behavior, and Immunity

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During CNS development, microglia transform from highly mobile amoeboid-like cells to primitive ramified forms and, finally, to highly branched but relatively stationary cells in maturity. The factors that control developmental changes in microglia are largely unknown. Because microglia detect and clear apoptotic cells, developmental changes in microglia may be controlled by neuronal apoptosis. Here, we assessed the extent to which microglial cell density, morphology, motility, and migration are regulated by developmental apoptosis, focusing on the first postnatal week in the mouse hippocampus when the density of apoptotic bodies peaks at postnatal day 4 and declines sharply thereafter. Analysis of microglial form and distribution in situ over the first postnatal week showed that, although there was little change in the number of primary microglial branches, microglial cell density increased significantly, and microglia were often seen near or engulfing apoptotic bodies. Time-lapse imaging in hippocampal slices harvested at different times over the first postnatal week showed differences in microglial motility and migration that correlated with the density of apoptotic bodies. The extent to which these changes in microglia are driven by developmental neuronal apoptosis was assessed in tissues from BAX null mice lacking apoptosis. We found that apoptosis can lead to local microglial accumulation near apoptotic neurons in the pyramidal cell body layer but, unexpectedly, loss of apoptosis did not alter overall microglial cell density in vivo or microglial motility and migration in ex vivo tissue slices. These results demonstrate that developmental changes in microglial form, distribution, motility, and migration occur essentially normally in the absence of developmental apoptosis, indicating that factors other than neuronal apoptosis regulate these features of microglial development.

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Section: Discussionmentioning

confidence: 99%

Developmental changes in microglial mobilization are independent of apoptosis in the neonatal mouse hippocampus

Eyo

Miner

Weiner

et al. 2016

Brain, Behavior, and Immunity

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“…In the aging retina, for example, microglia become less dynamic and consequently morphologically less ramified. This may lead to impairments in their surveillance ability [63, 64]. In the Hdc-KO mouse, striatal microglia present similar morphological abnormalities [46].…”

Section: Possible Mechanismsmentioning

confidence: 99%

Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS

Frick

Pittenger

2016

Journal of Immunology Research

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There is accumulating evidence that immune dysregulation contributes to the pathophysiology of obsessive-compulsive disorder (OCD), Tourette syndrome, and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). The mechanistic details of this pathophysiology, however, remain unclear. Here we focus on one particular component of the immune system: microglia, the brain's resident immune cells. The role of microglia in neurodegenerative diseases has been understood in terms of classic, inflammatory activation, which may be both a consequence and a cause of neuronal damage. In OCD and Tourette syndrome, which are not characterized by frank neural degeneration, the potential role of microglial dysregulation is much less clear. Here we review the evidence for a neuroinflammatory etiology and microglial dysregulation in OCD, Tourette syndrome, and PANDAS. We also explore new hypotheses as to the potential contributions of microglial abnormalities to pathophysiology, beyond neuroinflammation, including failures in neuroprotection, lack of support for neuronal survival, and abnormalities in synaptic pruning. Recent advances in neuroimaging and animal model work are creating new opportunities to elucidate these issues.

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“…These important functions are made possible by their ramified morphology (Morrison and Filosa, 2013), dynamic process movement (Davalos et al, 2005), consistent distribution throughout the brain (Lawson et al, 1990), and continuous input from neurons and astrocytes via small molecular messengers (i.e. fractalkine and S100β respectively) (Bianchi et al, 2010; Madry and Attwell, 2015). We previously reported that microglia morphology and phagocytic receptor CD11b are immediately changed by brain ischemia and therefore can be used as an indicator of an early microglia response to stroke (Morrison and Filosa, 2013).…”

mentioning

confidence: 99%

Sex differences in astrocyte and microglia responses immediately following middle cerebral artery occlusion in adult mice

Morrison

Filosa

2016

Neuroscience

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Epidemiological studies report that infarct size is decreased and stroke outcomes are improved in young females when compared to males. However, mechanistic insight is lacking. We posit that sex-specific differences in glial cell functions occurring immediately after ischemic stroke are a source of dichotomous outcomes. In this study we assessed astrocyte Ca2+ dynamics, aquaporin 4 (AQP4) polarity, S100β expression pattern, as well as, microglia morphology and phagocytic marker CD11b in male and female mice following 60 minutes of middle cerebral artery (MCA) occlusion. We reveal sex differences in the frequency of intracellular astrocyte Ca2+ elevations (F(1,86)=8.19, P=0.005) and microglia volume (F(1,40)=12.47, P=0.009) immediately following MCA occlusion in acute brain slices. Measured in fixed tissue, AQP4 polarity was disrupted (F(5,86)=3.30, P=0.009) and the area of non-S100β immunoreactivity increased in ipsilateral brain regions after 60 min of MCA occlusion (F(5,86)=4.72, P=0.007). However, astrocyte changes were robust in male mice when compared to females. Additional sex differences were discovered regarding microglia phagocytic receptor CD11b. In sham mice, constitutively high CD11b immunofluorescence was observed in females when compared to males (P=0.03). When compared to sham, only male mice exhibited an increase in CD11b immunoreactivity after MCA occlusion (P=0.006). We posit that a sex difference in the presence of constitutive CD11b has a role in determining male and female microglia phagocytic responses to ischemia. Taken together, these findings are critical to understanding potential sex differences in glial physiology as well as stroke pathobiology which are foundational for the development of future sex-specific stroke therapies.

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Receptors, Ion Channels, and Signaling Mechanisms Underlying Microglial Dynamics

Cited by 76 publications

References 74 publications

Developmental changes in microglial mobilization are independent of apoptosis in the neonatal mouse hippocampus

Developmental changes in microglial mobilization are independent of apoptosis in the neonatal mouse hippocampus

Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS

Sex differences in astrocyte and microglia responses immediately following middle cerebral artery occlusion in adult mice

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