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

Abstract

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.

Age‐specific function of α5β1 integrin in microglial migration during early colonization of the developing mouse cortex

“…Our observations are similar to what has been observed between postnatal ages P2 and P6 in the mouse hippocampus (Eyo, Miner, Weiner, & Dailey, 2016) and between 3.5 and 5 dpf in the zebrafish optic tectum (Svahn et al, 2013). Our observations are similar to what has been observed between postnatal ages P2 and P6 in the mouse hippocampus (Eyo, Miner, Weiner, & Dailey, 2016) and between 3.5 and 5 dpf in the zebrafish optic tectum (Svahn et al, 2013).…”

“…We observed a decrease in the microglial average migration speed over embryonic development and this resulted from both an increased idling time and a lower instantaneous speed. Our observations are similar to what has been observed between postnatal ages P2 and P6 in the mouse hippocampus (Eyo, Miner, Weiner, & Dailey, 2016) and between 3.5 and 5 dpf in the zebrafish optic tectum (Svahn et al, 2013). The decrease in average speed at E17.5 coincided with an increase in the immobile fraction of microglial cells and could indicate that some microglial cells acquire their final locations in the cortex between E13.5 and E17.5.…”

“…Nevertheless, microglia within the tissue depth did not show such behaviors. This indicates that deep tissue imaging, as performed in our study, is likely to allow analyzing behavior of the microglial population close to physiologic conditions (Eyo & Dailey, 2013;Eyo et al, 2016;Schiefer et al, 1999). It is important to note that microglial mobility in the in vivo developing zebrafish was also high (Sieger et al, 2012;Svahn et al, 2013).…”

Microglia and sexual differentiation of the developing brain: A focus on extrinsic factors

“…Secreted factors, such as colony‐stimulating factor 1 and interleukin‐34, are necessary for microglia viability (Elmore et al, ; Erblich, Zhu, Etgen, Dobrenis, & Pollard, ; Greter et al, ; Wang et al, ; Wei et al, ), and other factors, such as transforming growth factor‐beta, promote their maturation into an adult phenotype (Bohlen et al, ; Butovsky et al, ). Microglia colonization is influenced by a number of developmental phenomena—maturation of cell surface markers and secreted factors, progenitor cell proliferation, and apoptosis—in a brain‐region‐ and time‐dependent manner (Arnó et al, ; Ashwell, ; Eyo, Miner, Weiner, & Dailey, ; Ferrer et al, ; Hoshiko et al, ; Lelli et al, ; Mosher et al, ; Perry, Hume, & Gordon, ; Smolders et al, ). Together, these environmental signals serve to coordinate the timing of microglia entry and function in parallel with the maturation of specific brain regions.…”

Sex differences in microglial phagocytosis in the neonatal hippocampus

“…Microglia also remove synapses and dying cells via a process of engulfment and degradation, called phagocytosis (Cunningham et al, 2013; Schafer et al, 2012). Microglia target healthy progenitor cells as well as recently divided cells in the cerebral cortex after the peak in progenitor proliferation, and induce neuronal cell death during the peak period for apoptosis (Cunningham et al, 2013; Eyo et al, 2016; Wakselman et al, 2008). There are previous reports of sex differences in microglial morphology in the hippocampus, amygdala and preoptic area (Lenz et al, 2013; Schwarz et al, 2012).…”