Brain immune cells 'listen in' to neurons, offering new direction for neurological drug research

Microglia are immune cells best known as scavengers of the brain. Their immunological functions and roles in maintaining neural circuits have drawn interest in research into neurological disorders. But not all microglia are the same.

In a new study published in Nature, scientists from the Broad Institute of MIT and Harvard found that microglia cells “listen in” to neighboring neurons and change their density and molecular features accordingly.

Knowing how microglia respond to different neurons could open new venues to developing more targeted approaches to treating disorders like schizophrenia, which are associated with malfunctioned communications between microglia and neurons.

“You would no longer have to treat, for instance, microglia as one blanket cell type when trying to affect the brain,” Jeffrey Stogsdill, Ph.D., the study’s first author, explained in a statement. “We can target very specific states, or we can target very specific subtypes of neurons with the ability to change specific states of microglia.”

The Broad team used single-cell and spatial RNA transcripts profiling to understand the molecular signatures and locations of various microglia populations in mice brains.

They found that shortly after birth, microglia were evenly distributed throughout all layers in the cerebral cortex, which is a region of the brain responsible for skilled motor function, sensory perception and cognition. However, microglia density started to vary in different layers later, the researchers found.

Using two genetically modified mice with the composition of neurons altered in specific cortex layers, the researchers found that microglia density is correlated with the composition of neurons in each layer.

Further RNA sequencing analysis identified several distinct microglia clusters based on their genetic signatures. Some microglia populations are broadly distributed throughout the cortex, whereas others are mainly found in specific layers, the team found.

The scientists then changed the composition of neuron types in layers. Doing so altered the genetic markers of microglia, as the immune cells matched their states with the neurons nearby in the new locations, the team found. This confirmed that the neurons—not the physical location—were influencing microglia, .

Microglia’s capabilities to clear cell debris and regulate neurons have made them popular research targets in neurological disorders. For example, a research group led by the Icahn School of Medicine at Mound Sinai found that microglia could sense and suppress excessive neuronal activation, which is behind behavioral problems in neurodegenerative diseases.

In the current study, the Broad team has built a molecular atlas detailing pairs of protein receptors and binders that were influenced by neuron subtypes and microglia states. Such a map could enable future research into neuron-microglia interactions and potentially lead to possible drug targets, the team said.

The researchers now plan to further examine the functional differences among the microglia in the different layers.