The immune cells that patrol the human brain take far longer to grow up than anyone had documented — as long as four to eight years, compared with about three weeks in mice — according to a new study from Columbia University's Zuckerman Institute. The researchers say the extended timeline may be linked to a gene duplicated only in humans, and could help explain why our brains are able to support unusually sophisticated cognition.
The cells in question, called microglia, are the brain's resident immune cells; beyond fighting infection, they help sculpt developing neural circuits by pruning weak synaptic connections and supporting the wiring of new ones. In the study, published in the journal Neuron, researchers led by Carlos Diaz-Salazar and Franck Polleux compared microglial development in mice and in human cells, and found that a human-specific duplicate of a gene called SRGAP2 is nearly ten times more abundant in microglia than in neurons. SRGAP2 was already known to slow the maturation of human neurons relative to other species; the new work suggests it does something similar — and more pronounced — in microglia.
A gene tied to human brain evolution
Polleux's lab has studied SRGAP2 for more than 15 years as one of several dozen genes that exist in duplicate only in humans, likely arising from ancient genome errors that were preserved by natural selection. Earlier work from the same group linked the gene to the slower pace and higher density of synapse formation in human neurons compared with other primates. The new findings extend that story to the immune cells that help build and refine those circuits in the first place, raising the possibility that a slower, more deliberate microglial "editing" process — stretched over years rather than weeks — gives the developing human brain more time to fine-tune its wiring.
"This slow development may help human microglia influence the human brain in ways that enable our powerful cognitive abilities."
— Carlos Diaz-Salazar, Columbia University's Zuckerman Institute
The researchers caution that the link between SRGAP2 duplication and enhanced cognition is, for now, a hypothesis supported by correlated timing and gene-dosage evidence rather than a directly proven causal mechanism. Much of the underlying molecular work was conducted in mice engineered to carry the human gene duplicate and in human cells rather than in living human brains, which are far harder to study directly during early development.
The team says a natural next step is examining what happens when microglial maturation goes wrong — either too fast or too slow — and whether that contributes to neurodevelopmental conditions such as autism, or to neurodegenerative disease later in life, when microglia are already known to play a role in conditions like Alzheimer's. Because human microglia take years rather than weeks to reach maturity, the researchers note, there is a comparatively long window during early childhood when disruptions to that process — from infection, inflammation or other stressors — could plausibly affect brain development, though that connection remains to be tested directly.