Immune cells known as microglia, long thought to be activated in the brain only when fighting infection or injury, are constantly active and likely play a central role in one of the most basic, central phenomena in the brain - the creation and elimination of synapses. The findings, publishing next week in the online, open access journal PLoS Biology, catapult the humble microglia cell from its well-recognized duty of protecting the brain to direct involvement in creating the cellular networks at the core of brain behavior. Its apparent role as an architect of synapses - junctions between brain cells called neurons - comes as a surprise to researchers long accustomed to thinking of microglia as cells focused exclusively on keeping the brain safe from threats.
The research helps move microglia up into the pantheon of brain cells known to affect brain signaling. Years ago, brain signaling was thought to be the exclusive domain of neurons. During the last two decades, scientists have found that astrocytes also have vast signaling networks. Now, microglia also seem to be an important player in the brain's ability to adapt immediately and constantly to the environment and to shift its resources accordingly.
"When scientists talk about microglia, the talk is almost always about disease. Our work suggests that microglia may actively contribute to learning and memory in the healthy brain, which is something that no one expected," said Ania Majewska, Ph.D., the neuroscientist at the University of Rochester Medical Center who led the work.
The group's paper is a detailed look at how brain cells interact with each other and react to their environment swiftly, reaching out constantly to form new links or abolish connections. First author Marie-Ève Tremblay, Ph.D., a post-doctoral associate in Majewska's lab, used two sophisticated imaging techniques to get an unprecedented look at microglia in the brain. She used immunoelectron microscopy and two-photon microscopy to look at how microglia interact with synapses in the brains of healthy mice as their environment changed. In the experiments, the scientists looked into the brain while the mice were 1) on a normal cycle of light and dark, 2) while the mice were in the dark for several days, and 3) when the mice went back to a normal light/dark cycle. Their study reveals a high level of activity among microglia in response to changes in visual experience. This shows that even under nonpathological conditions, microglia are actively participating in neuronal functions.
Specifically, Majewska's group found that microglia showed a great deal of structural and morphological plasticity. When the lights were off, microglia contacted more synapses, were more likely to reach toward a particular type of synapse, and tended to be larger. When the lights came back on, most of those changes reversed. In time-lapse video of their experiments, microglia seemed to dance across the screen, extending their processes dynamically across their local environment. Tremblay and Majewska showed that microglia touch and wrap around synapses constantly and may have some say in deciding which synapses will survive. Microglia also appear key to creating or changing the extracellular space around synapses, a factor that would profoundly affect synapse function. The team even found indications that microglia may be involved in destroying synapses. Eliminating dendritic spines is one way to destroy synapses, and in their study, Majewska's group found that dendritic spines that were touched by microglial processes were more than three times as likely to be eliminated within the next two days compared to spines that were not.
The findings are timely for scientists who are increasingly studying links between the nervous and immune systems, Tremblay said. The role of microglial cells are now being studied in the context of a number of diseases, including Parkinson's, Alzheimer's, schizophrenia, and even autism.
Former technician Rebecca Lowery is also an author of the paper. Also contributing were Gayle Schneider and Karen Bentley of the Electron Microscope Research Core Facility.
Funding: This work was supported by grants from the National Institutes of Health (EY019277), Whitehall Foundation, the Alfred P. Sloan Foundation, and a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund to AKM. MÈT is funded by a Fonds de la recherche en santé du Québec (FRSQ) postdoctoral training award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests statement: The authors declare that no competing interests exist.
Citation: Tremblay M-E, Lowery RL, Majewska AK (2010) Microglial Interactions with Synapses Are Modulated by Visual Experience. PLoS Biol 8(11): e1000527. doi:10.1371/journal.pbio.1000527
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