Physiological Role for Microglial Surveillance Uncovered

Why microglia are constantly surveying their environment is explained in a paper published recently in Nature Neuroscience. An important part of the brain's immune system, this continuous and rapid surveillance occurs in your brain all the time, without the presence of disease, and whether you are awake or asleep. The longstanding theory has been that microglia perform this surveillance to sense invasion by an infectious agent or to sense trauma.

"This never made sense to me," says senior author Katerina Akassoglou from Gladstone Institutes. "Why would a cell expend so much energy for something that might never happen? I always thought there must be another reason for microglia to be moving all the time, likely related to a normal function in the brain."

A turning point in the study happened when a first author on the study, Victoria Rafalski, unexpectedly observed a mouse, in which the process of microglial brain survillance was blocked, having a seizure. "That's when we realized that with microglia not functioning properly, mice were having spontaneous seizures," says Rafalski. "It was our first indication that surveillance by these cells might suppress seizure activity. It also gave us a hint as to why they needed to move constantly—suppressing seizures may be a nonstop necessity in the brain."

Combining advanced microscopy and image analysis, the team was able to observe the interaction between microglia and active neurons in a live brain. They discovered that microglia are not extending their branches at random. Instead, microglia reach out primarily to active neurons, one after another, while paying less attention to non-active neurons. Importantly, they noticed that when microglia touch an active neuron, that neuron's activity does not increase further.

"Microglia seem to sense which neuron is about to become overly active, and keep it in check by making contact with it, which prevents that neuron's activity from escalating," explains the study's other first author, Mario Merlini. "In contrast, in our mouse model where microglia movements are frozen, we found that the activity of nearby neurons keeps increasing, a bit like a heater with a broken thermostat. This changed our thinking on how neuronal activity is regulated in the brain. Instead of an on-off switch, microglia are the brain's thermostat, controlling excessive neuronal activity".

These findings helped the team discover a physiological role for microglial surveillance; microglia are essential for maintaining neuronal activity within a normal range by preventing neurons from becoming overactive, or hyperexcitable. These findings could open new therapeutic avenues for several diseases, given that hyperexcitability is a feature of many neurological disorders, including Alzheimer's disease, epilepsy, and autism.