Morphological and Phagocytic Profile of Microglia in the Developing Rat Cerebellum

Pérez-Pouchoulén, Miguel; VanRyzin, Jonathan W.; McCarthy, Margaret M.

doi:10.1523/eneuro.0036-15.2015

Cited by 82 publications

(68 citation statements)

References 74 publications

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“…We looked at two ages: at P11, the peak of developmental torpedo density, and at P30 ( Figure 3A ), when torpedoes are larger but less numerous. We found that microglia density in the granule cell layer increased significantly over this period ( Figure 3B ; P11: 6.52 ± 0.37 cells/10 6 μm 3 ; P30: 7.71 ± 0.44 cells/10 6 μm 3 ; significantly different, P = 0.045), likely because microglia density throughout the cerebellum overall increases across development (Perez-Pouchoulen et al, 2015). To determine whether microglia were enriched around torpedoes, which might suggest that they are involved in axonal refinement, we measured the local density of microglia around torpedoes ( Figure 3C ) and compared this density to that around Purkinje cell axons that are not in the proximity of a torpedo ( Figure 3C shows two examples for each).…”

Section: Resultsmentioning

confidence: 86%

Transient Developmental Purkinje Cell Axonal Torpedoes in Healthy and Ataxic Mouse Cerebellum

Ljungberg

Lang-Ouellette

Yang

et al. 2016

Front. Cell. Neurosci.

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Information is carried out of the cerebellar cortical microcircuit via action potentials propagated along Purkinje cell axons. In several human neurodegenerative diseases, focal axonal swellings on Purkinje cells – known as torpedoes – have been associated with Purkinje cell loss. Interestingly, torpedoes are also reported to appear transiently during development in rat cerebellum. The function of Purkinje cell axonal torpedoes in health as well as in disease is poorly understood. We investigated the properties of developmental torpedoes in the postnatal mouse cerebellum of wild-type and transgenic mice. We found that Purkinje cell axonal torpedoes transiently appeared on axons of Purkinje neurons, with the largest number of torpedoes observed at postnatal day 11 (P11). This was after peak developmental apoptosis had occurred, when Purkinje cell counts in a lobule were static, suggesting that most developmental torpedoes appear on axons of neurons that persist into adulthood. We found that developmental torpedoes were not associated with a presynaptic GABAergic marker, indicating that they are not synapses. They were seldom found at axonal collateral branch points, and lacked microglia enrichment, suggesting that they are unlikely to be involved in axonal refinement. Interestingly, we found several differences between developmental torpedoes and disease-related torpedoes: developmental torpedoes occurred largely on myelinated axons, and were not associated with changes in basket cell innervation on their parent soma. Disease-related torpedoes are typically reported to contain neurofilament; while the majority of developmental torpedoes did as well, a fraction of smaller developmental torpedoes did not. These differences indicate that developmental torpedoes may not be functionally identical to disease-related torpedoes. To study this further, we used a mouse model of spinocerebellar ataxia type 6 (SCA6), and found elevated disease-related torpedo number at 2 years. However, we found normal levels of developmental torpedoes in these mice. Our findings suggest that the transient emergence of Purkinje cell axonal torpedoes during the second postnatal week in mice represents a normal morphological feature in the developing cerebellar microcircuit.

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Section: Resultsmentioning

confidence: 86%

Transient Developmental Purkinje Cell Axonal Torpedoes in Healthy and Ataxic Mouse Cerebellum

Ljungberg

Lang-Ouellette

Yang

et al. 2016

Front. Cell. Neurosci.

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“…There is no sex difference in the number of apoptotic cells, and hippocampal apoptosis quickly decreases after the first postnatal day (Mosley et al, 2016; Wakselman et al, 2008). Research in the cerebellum has also found that microglia did not preferentially target dying cells during the first three weeks of life (Perez-Pouchoulen et al, 2015). Additionally, microglia can induce death in healthy cells before phagocytizing them (Guadagno et al, 2015; Neher et al, 2014; Wakselman et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Sex differences in microglial phagocytosis in the neonatal hippocampus

Nelson

Warden

Lenz

2017

Brain, Behavior, and Immunity

159

136

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Microglia regulate brain development through many processes, such as promoting neurogenesis, supporting cell survival, and phagocytizing progenitor, newly-born, and dying cells. Many of these same developmental processes show robust sex differences, yet very few studies have assessed sex differences in microglia function during development. Hormonally-induced sexual differentiation of the brain occurs during the perinatal period, thus we examined sex differences in microglial morphology, phagocytosis, and proliferation in the hippocampus during the early postnatal period. We found that the neonatal female hippocampus had significantly more microglia with phagocytic cups than the male hippocampus. We subsequently found that female microglia phagocytized more neural progenitor cells and healthy cells compared to males, but there were no sex differences in the number of newly-born or dying cells targeted by microglial phagocytosis. We found that the number of phagocytic microglia in females was reduced to male-typical levels by treatment with estradiol, the hormone responsible for masculinizing the rodent brain. Females also had higher expression of several phagocytic pathway genes in the hippocampus compared to males. In contrast to robust sex differences in phagocytic microglia, we found no sex differences in the number of microglia with amoeboid, transitioning, or ramified morphologies or differences in three-dimensional reconstructions of microglial morphology. While we did not find a baseline sex difference in microglial proliferation during or following the prenatal gonadal hormone surge in males, we found that estradiol treatment increased microglia proliferation in females. Overall, these data show that there are important sex differences in microglia function in the hippocampus during the early neonatal period.

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“…Inhibition of endoplasmic reticulum Ca2-ATPase by thapsigargin, down-regulation of complement receptor 3 and major histocompatibility complex I and II antigen-like immunoreactivity accompanied ramification of microglia in vitro [48, 49]. In the postnatal mouse brain microglia are initially amoeboid but as brain development proceed they gradually undergo a transition into a ramified state and a transcriptional factor Runx1 was found to be expressed in postnatal amoeboid microglia but it was down regulated in adult ramified microglia [50, 51]. This ramification process is recapitulated in reverse during microglia activation in response to brain injury or disease [52–54].…”

Section: Discussionmentioning

confidence: 99%

The adenosine generating enzymes CD39/CD73 control microglial processes ramification in the mouse brain

et al. 2017

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Microglial cells invade the brain as amoeboid precursors and acquire a highly ramified morphology in the postnatal brain. Microglia express all essential purinergic elements such as receptors, nucleoside transporters and ecto-enzymes, including CD39 (NTPDase1) and CD73 (5'-nucleotidase), which sequentially degrade extracellular ATP to adenosine. Here, we show that constitutive deletion of CD39 and CD73 or both caused an inhibition of the microglia ramified phenotype in the brain with a reduction in the length of processes, branching frequency and number of intersections with Sholl spheres. In vitro, unlike wild-type microglia, cd39-/- and cd73-/- microglial cells were less complex and did not respond to ATP with the transformation into a more ramified phenotype. In acute brain slices, wild-type microglia retracted approximately 50% of their processes within 15 min after slicing of the brain, and this phenomenon was augmented in cd39-/- mice; moreover, the elongation of microglial processes towards the source of ATP or towards a laser lesion was observed only in wild-type but not in cd39-/- microglia. An elevation of extracellular adenosine 1) by the inhibition of adenosine transport with dipyridamole, 2) by application of exogenous adenosine or 3) by degradation of endogenous ATP/ADP with apyrase enhanced spontaneous and ATP-induced ramification of cd39-/- microglia in acute brain slices and facilitated the transformation of cd39-/- and cd73-/- microglia into a ramified process-bearing phenotype in vitro. These data indicate that under normal physiological conditions, CD39 and CD73 nucleotidases together with equilibrative nucleoside transporter 1 (ENT1) control the fate of extracellular adenosine and thereby the ramification of microglial processes.

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Morphological and Phagocytic Profile of Microglia in the Developing Rat Cerebellum

Cited by 82 publications

References 74 publications

Transient Developmental Purkinje Cell Axonal Torpedoes in Healthy and Ataxic Mouse Cerebellum

Transient Developmental Purkinje Cell Axonal Torpedoes in Healthy and Ataxic Mouse Cerebellum

Sex differences in microglial phagocytosis in the neonatal hippocampus

The adenosine generating enzymes CD39/CD73 control microglial processes ramification in the mouse brain

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