New clues to how human brain connections take shape
A new study from Karolinska Institutet, published in Nature Communications, reveals an unexpected role for immature glial cells known as oligodendrocyte progenitor cells (OPCs) in shaping the developing human brain.
Using a laboratory-grown model of human brain tissue, the research team uncovered a distinct molecular mechanism through which OPCs contribute to the removal of synapses, a key process that helps refine neural circuits during development.
As the brain forms, it generates an abundance of synapses—connections between neurons—many of which must later be eliminated to establish efficient and accurate neural networks. Until now, this synaptic pruning was believed to be carried out primarily by microglia, the brain’s immune cells, and by astrocytes, another major glial cell population.
Working with advanced human brain organoids containing neurons, microglia, astrocytes, and cells of the oligodendrocyte lineage, researchers observed that OPCs make contacts with synapses and can internalise synaptic material. While similar behaviours have been reported in mice and zebrafish, this is the first demonstration of the process in a human model system.
By combining single-cell transcriptomics with high-resolution imaging, the team identified a specific signalling pathway through which GAS6, released by neurons and microglia, modulates synapse uptake in a subset of OPCs that express its receptor AXL. Disrupting this pathway markedly reduced the ability of OPCs to internalize synaptic material.
"Our work shows that human OPCs aren't just future insulators - they also actively participate in refining neural circuits during development” says Asimenia Gkogka, first author and doctoral student in Carl Sellgren’s research group at the Department of Physiology and Pharmacology, Karolinska Institutet. “Identifying the GAS6-AXL pathway as one of the molecular cues involved gives us a starting point for exploring how this process might be altered in neurodevelopmental conditions.”
Co-senior author Dr. Samudyata in the same research team adds: “Our brain organoid model allows us to observe these cell-to-cell interactions over time, offering unique insight into how different glial populations work together to shape the developing human brain.”
The findings highlight OPCs as an underappreciated contributor to early human circuit formation and provides new tools for studying how disruptions in synapse refinement may relate to psychiatric and neurodevelopmental disorders.