Mapping tool reveals shape-changing secrets of microglia

Microglia have distinct morphologies depending on where they reside in the mouse brain, according to a new approach which reveals nuances on the shape of the cells. This shape also changes with development and varies by sex, researchers show in data that could help understand the role of microglia in conditions such as autism.

Microglia are immune cells that support healthy brain development. Considered the brain gardeners Where maidsthey constantly monitor their surroundings, ready to activate when their services are needed to prune synapses or clean up cellular debris.

Microglial cell function goes awry in people with autism, according to a theory about the disease. Microglia in the brains of people with autism tend to have dysregulated genesand autism model mice have a disproportionate number of microglia in a activated state. But researchers don’t yet know how microglia morphology relates to function or how it changes during development, so it’s been difficult to assess exactly what’s atypical in people with autism.

One challenge is figuring out how to track cell changes in the first place, says Sandra Siegert, Assistant Professor of Life Sciences at the Austrian Institute of Science and Technology in Klosterneuburg. Although it is often possible to distinguish between activated and non-activated microglia – the former tend to be round with short appendages, whereas the non-activated cells usually have long, thin arms that branch into numerous directions – many cells exist in an intermediate state.

As a result, “we don’t know which feature is the most important feature to characterize the shape of microglia,” says Siegert. So she and her colleagues found a way to mathematically simplify the 3D shape of a microglial cell while retaining as much information as possible, which they used to analyze more than 40,000 individual cells from seven brain regions in male and female mice at different stages of development. .

The approach could “shed light on circuitry that might be involved” in neurodevelopmental conditions such as autism, says Lior Brimbergassistant professor of neuroimmunology at the Feinstein Institutes for Medical Research in Manhasset, New York, who was not involved in the work.

Siegert says she and her colleagues wanted to assess how microglia change shape in response to exposure to ketamine, a drug used to anesthetize laboratory animals. Repeated exposure to ketaminethe team found in a previous study, allows microglia to remove a structure called the perineuronal net interneurons, increasing the synaptic plasticity of neurons. But when the team used standard methods to assess changes in microglial cell shape that might explain the change in function, they found nothing.

Instead, they decided to track cell morphology using methods from the mathematical field of topology. They developed an algorithm that tracks the length of a cell’s branches, starting with the ends farthest from the cell body. At each branch, the software determines the longest branch and the shortest branch. It records the length of the shorter arm and then continues to track the length of the longer arm. The resulting reading looks like a horizontal barcode, with a stack of staggered lines that represent the length of each branch and its relationship to the others on the cell.

The team then converted each barcode to an image and processed the image pool to capture the most informative dimensions. Microglia from the same brain region have a similar morphology, tracings of the results of each cell were revealed. Cells from the primary somatosensory cortex moved closer together, for example, while cells from the cochlear nucleus and cerebellum formed their own clusters, suggesting that the approach captures significant regional differences in microglial shape. The results published in September in Natural neuroscience.

Graph showing shape similarities in microglia

Similar forms: Microglia from the same brain region (represented by color) cluster together when analyzed using the new method, suggesting that they have similar morphology.

Microglial morphology changes with development in a region-specific manner, according to analysis of cells from 7-, 15-, and 22-day-old mice, as well as adult animals. Cells from adult female and male mice also formed their own distinct clusters for most brain regions, indicating sex differences in microglia.

When Siegert and colleagues applied this same approach to microglia repeatedly exposed to ketamine, they found that multiple exposures moved cells away from the mature, non-activated profile towards the activated profile seen in the brains of younger mice.

With the previous approach, “it’s not so overwhelmingly obvious that something is going on morphologically,” says Siegert. “But now, with our strategy, it is possible to track down this kind of morphological change.”

gHaving a clear picture of how and when microglia change morphology in animal models of autism “will be a huge advantage,” Brimberg says.

Single-cell RNA sequencing can differentiate between activated and non-activated microglia, but it’s not yet clear how RNA-seq data correlates with subtle differences in cell shapes, Brimberg notes. In the future, it would also be useful to compare RNA sequencing data with morphology data to see how they overlap, she adds.

Researchers plan to continue studying how microglia morphology predicts function, from identifying changes after repeated exposure to ketamine to tracking the shape of cells in the brains of mice that model conditions such as disease. of Alzheimer’s,” says Siegert.

“Morphology was so important” in categorizing cells and comparing conditions, she says. “So it’s essential” to understand.

This article was originally published on Spectrumthe main site for autism research information.

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