Microglia are the brain’s most abundant immune cells. They help protect the brain from harmful invaders, clear away damaged neurons, and support normal brain development. Researchers at Columbia’s Zuckerman Institute have now found for the first time that human microglia, much like human neurons, mature far more slowly than comparable cells in other animals.
“This slow development may help human microglia influence the human brain in ways that enable our powerful cognitive abilities,” said Carlos Diaz-Salazar, PhD, the lead author of a new Neuron study on the subject, who carried out the work while in the lab of Franck Polleux, PhD.
A Human-Specific Gene With an Unusual Role
The Polleux lab has spent more than 15 years studying SRGAP2, one of several dozen genes that were duplicated specifically in humans. The group’s broader goal is to understand the biological features that distinguish the human brain from those of other animals.
Earlier work by Dr. Polleux showed that human-specific copies of SRGAP2 increase the number of synapses, or connections, made by neurons while also causing those synapses to mature very slowly. Both traits are distinctive features of human neurons among mammals. The result is a denser and stronger network of neuronal connections that may enhance the brain’s ability to process and store information.
In the new research, Dr. Diaz-Salazar found something unexpected. Human-specific copies of SRGAP2 were nearly 10 times more abundant in microglia than in neurons.
“So the question was, ‘Why on Earth is this gene so active in microglia?'” recalled Dr. Polleux, a principal investigator at the Zuckerman Institute.
Microglia Help Shape Developing Brain Circuits
Over roughly the past two decades, scientists have learned that microglia do much more than fight infections and help repair brain damage. These cells, which account for 5 to 10 percent of brain cells, also help organize the developing brain.
During development, microglia influence which synapses neurons retain and which ones are eliminated. They can also make synapses more or less responsive, helping fine-tune communication within brain circuits.
Experiments using mice and human cells showed that the human-specific copies of SRGAP2 dramatically slow the development of human microglia. Human microglia take about four to eight years to mature, while microglia in mice reach maturity in roughly three weeks.
“This gene helps control the developmental tempo of neurons, and nature has also selected it to control the development of microglia that are so crucial to neuron development, so they are in sync during development,” said Dr. Diaz-Salazar, who is now a researcher at the Hospital del Mar Medical Research Institute in Barcelona.
Why the Human Brain Takes So Long To Mature
Compared with the brains of other mammals, the human brain develops over an unusually long period. Scientists refer to this extended developmental timetable as neoteny, and it is thought to play an important role in the emergence of advanced human cognitive abilities.
The new findings suggest that SRGAP2 may help coordinate this slow developmental pace across multiple kinds of brain cells, including neurons and microglia. The researchers now want to determine exactly how the gene promotes neoteny in these cells and in other parts of the brain.
“We want to understand all the elements that help make up the human brain to understand what makes us unique from an evolutionary standpoint,” Dr. Polleux said. “Because scientists have recently found that microglia are involved in neurodevelopmental disorders and neurodegenerative diseases, our findings get us a step closer to understanding what makes human microglia special in the context of brain diseases.”
