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Microglia: Key Elements in Neural Development, Plasticity, and Pathology

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Abstract

A century after Cajal identified a “third element” of the nervous system, many issues have been clarified about the identity and function of one of its major components, the microglia. Here, we review recent findings by microgliologists, highlighting results from imaging studies that are helping provide new views of microglial behavior and function. In vivo imaging in the intact adult rodent CNS has revolutionized our understanding of microglial behaviors in situ and has raised speculation about their function in the uninjured adult brain. Imaging studies in ex vivo mammalian tissue preparations and in intact model organisms including zebrafish are providing insights into microglial behaviors during brain development. These data suggest that microglia play important developmental roles in synapse remodeling, developmental apoptosis, phagocytic clearance, and angiogenesis. Because microglia also contribute to pathology, including neurodevelopmental and neurobehavioral disorders, ischemic injury, and neuropathic pain, promising new results raise the possibility of leveraging microglia for therapeutic roles. Finally, exciting recent work is addressing unanswered questions regarding the nature of microglial-neuronal communication. While it is now apparent that microglia play diverse roles in neural development, behavior, and pathology, future research using neuroimaging techniques will be essential to more fully exploit these intriguing cellular targets for effective therapeutic intervention applied to a variety of conditions.

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Acknowledgements

Supported by grants from the UI Biological Sciences Funding Program (to MED), American Heart Association (0950160G to MED), the National Institutes of Health (AA018823 to MED), and the Iowa Center for Molecular Auditory Neuroscience (ICMAN) though NIH Grant P30 DC010362. All experiments were performed in accordance with the Institutional Animal Care and Use Committee (IACUC) and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The authors declare that they have no conflict of interest.

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  1. Ukpong B. Eyo

    Present address: Department of Cell Biology and Neuroscience, Rutgers University, B333 Nelson Labs, 604 Allison Road, Piscataway, NJ, 08854–6999, USA

Authors and Affiliations

  1. Department of Biology, University of Iowa, Iowa City, IA, 52242, USA

    Ukpong B. Eyo & Michael E. Dailey

  2. Department of Biology, 369 Biology Building, University of Iowa, Iowa City, IA, 52242–1324, USA

    Michael E. Dailey

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  1. Ukpong B. Eyo
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Movie 1

Time-lapse confocal sequence from a live mouse hippocampal tissue slice showing a microglial cell (arrow) extending a branch to contact and phagocytose a nearby injured cell (arrowhead). The tissue slice was derived from a reporter mouse line (CX3CR1+/GPF) in which microglia express green fluorescent protein (GFP). Injured cells were labeled with Sytox, a membrane-impermeant DNA-binding dye that labels the nuclei of dead cells. Original images were taken at 3 min intervals. Time is shown in hr:min from the start of imaging. (AVI 3013 kb)

Movie 2

Rotation movie showing 3D relationships of microglia and apoptotic cells in the developing mouse hippocampus. Microglia (green) are expressing GFP. Early stage apoptotic cells (blue) are labeled with antibodies to cleaved caspase-3. Late stage apoptotic bodies are labeled with PSVue (red), which binds to phosphatidylserine lipids exposed on the surface of apoptotic cells. Note the wrapping of microglial processes around the soma of an early stage apoptotic pyramidal neuron (upper arrow). Late stage apoptotic bodies are engulfed by processes of phagocytosing microglia (lower arrow). (AVI 9845 kb)

Movie 3

Time-lapse sequence shows that flufenamic acid (FFA, 100 μM), a non-steroidal anti-inflammatory drug (NSAID), modulates microglia motility in a neonatal mouse hippocampal tissue slice. Microglia express GFP in this tissue slice derived from GFP-reporter mouse (CX3CR1+/GPF). Images on the left show raw fluorescence. Images on the right are “difference images,” which depict any changes in cell shape between sequential time points as white. Note the decline in microglial motility upon application of FFA, with slow recovery after washout. (AVI 2164 kb)

Movie 4

Time-lapse multiphoton imaging sequence shows rapid mobilization of microglia to injured neurons in P2X7 receptor null mice. Focal tissue injury was induced along a line by brief exposure to high intensity laser light (white line between white arrowheads). Within minutes, injured cells begin to take up a membrane-impermeable red fluorescent DNA-binding dye (ToPro3), and nearby microglia extend branches toward the laser damaged cells. Within a couple of hours, activated microglia have migrated and accumulated near the injured cells. Microglia respond to tissue injury even though they lack the P2X7 purinoceptor in these P2X7−/− mice. Time is shown in hr:min. (AVI 3706 kb)

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Eyo, U.B., Dailey, M.E. Microglia: Key Elements in Neural Development, Plasticity, and Pathology. J Neuroimmune Pharmacol 8, 494–509 (2013). https://doi.org/10.1007/s11481-013-9434-z

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