Animal models for studying microglia: The first, the popular, and the new.
Sieger, D. & Peri, F.
Glia. 2013 Jan;61(1):3-9. doi: 10.1002/glia.22385. Epub 2012 Sep 17.
Microglia, the resident phagocytes of brain, have been intensively studied since their discovery in the 1920s. There is no doubt that the possibility of culturing microglia in vitro has advanced enormously our understanding of these cells. However, as we know today, that microglia react to even small changes in the brain, it is crucial to also study these cells by preserving as much as possible their natural environment. Nowadays, advances in imaging technologies and transgenic cell labeling methods allow the direct observation of cells at work. These in vivo approaches have already changed our view on microglia by showing that these cells are active even in the healthy adult brain. As today, there is upcoming evidence that microglia can directly influence neuronal activity, understanding their roles and, in particular, their interactions with neurons is of great importance. The aim of this review is to illustrate three animal models that are currently used for microglial research and to discuss their characteristics and advantages by presenting recent achievements in microglial research. In our view the availability of different systems for studying microglia will lead to a more comprehensive understanding of their functions.
Long-range Ca2+ waves transmit brain-damage signals to microglia.
Sieger, D., Moritz, C., Ziegenhals, T., Prykhozhij, S. & Peri, F.
Dev Cell. 2012 Jun 12;22(6):1138-48. doi: 10.1016/j.devcel.2012.04.012. Epub 2012May 24.
Microglia are the resident phagocytes of the brain that are responsible for the clearance of injured neurons, an essential step in subsequent tissue regeneration. How death signals are controlled both in space and time to attract these cells toward the site of injury is a topic of great interest. To this aim, we have used the optically transparent zebrafish larval brain and identified rapidly propagating Ca2+ waves that determine the range of microglial responses to neuronal cell death. We show that while Ca2+-mediated microglial responses require ATP, the spreading of intercellular Ca2+ waves is ATP independent. Finally, we identify glutamate as a potent inducer of Ca2+-transmitted microglial attraction. Thus, this real-time analysis reveals the existence of a mechanism controlling microglial targeted migration to neuronal injuries that is initiated by glutamate and proceeds across the brain in the form of a Ca2+ wave.
Microglia in the developing brain: from immunity to behaviour.
Schlegelmilch, T., Henke, K. & Peri, F.
Curr Opin Neurobiol. 2011 Feb;21(1):5-10. doi: 10.1016/j.conb.2010.08.004.
For decades, microglia, the resident macrophages of the brain, have been recognized mostly for their role in several, if not all, pathologies affecting the brain. However, several studies under physiological conditions demonstrate that microglial function is indispensable also in the healthy brain. Indeed, microglia implement key functions already during development, such as the clearance of the huge amount of neurons that are produced in large excess in the embryo and later die of apoptosis. Beside these classical functions, however, novel roles are emerging that strikingly link microglia with higher order brain functions and show that these cells can ultimately influence behaviour. Therefore a detailed understanding of microglia under physiological conditions may open unprecedented perspectives in the prevention and treatment of neuropsychiatric diseases.
Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo.
Peri, F. & Nusslein-Volhard, C.
Cell. 2008 May 30;133(5):916-27.
A significant proportion of neurons in the brain undergo programmed cell death. In order to prevent the diffusion of damaging degradation products, dying neurons are quickly digested by microglia. Despite the importance of microglia in several neuronal pathologies, the mechanism underlying their degradation of neurons remains elusive. Here, we exploit a microglial population in the zebrafish to study this process in intact living brains. In vivo imaging reveals that digestion of neurons occurs in compartments arising from the progressive fusion of vesicles. We demonstrate that this fusion is mediated by the v0-ATPase a1 subunit. By applying live pH indicators, we show that the a1 subunit mediates fusion between phagosomes and lysosomes during phagocytosis, a function that is independent of its proton pump activity. As a real-time description of microglial phagocytosis in vivo, this work advances our understanding of microglial-mediated neuronal degeneration, a hallmark of many neuronal diseases.