Summary: A study reveals that human microglial cells mature significantly slower than those of other animals, driven by human-specific duplications of the SRGAP2 gene.
The study demonstrates that human microglia require four to eight years to reach full maturity, compared to approximately three weeks in mice. This prolonged developmental tempo (neoteny) aligns microglial maturation with human neuronal development.
Because microglia actively prune synapses and refine circuit responsiveness during development, this synchronized neoteny represents a critical evolutionary mechanism supporting human cognitive complexity, while offering new insights into neurodevelopmental and neurodegenerative disorders.
Key Facts
- Microglial Neoteny: Human microglia exhibit extreme developmental delay, taking four to eight years to mature fully, whereas mouse microglia achieve complete maturation in roughly three weeks.
- SRGAP2 Duplication Abundance: Human-specific duplicates of the $SRGAP2$ gene are nearly 10 times more abundant in microglia than in human neurons.
- Synchronized Developmental Tempo: The expression of duplicated $SRGAP2$ ensures that microglial maturation is temporally synchronized with human neuronal neoteny, allowing coordinated synaptic formation and pruning across childhood.
- Synaptic Refinement Mechanics: During brain development, microglia make up 5 to 10 percent of brain cells, actively selecting which neuronal synapses to retain or discard and regulating circuit responsiveness.
- Disease Relevance: Because microglia are implicated in neurodevelopmental conditions (such as autism spectrum disorder) and neurodegenerative diseases (such as Alzheimer’s), human-specific microglial maturation timelines provide a baseline for understanding human brain disorders.
Source: Zuckerman Institute
Microglia are the most common immune cells in the brain, where they defend against intruders and engulf damaged neurons. Now scientists at Columbia’s Zuckerman Institute have for the first time discovered that, just like human neurons, human microglia mature especially slowly compared to those 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 took part in this research while at the lab of Franck Polleux, PhD.
Focused on what makes humans special, the Polleux lab has investigated the gene SRGAP2 for more than 15 years, one of several dozen genes duplicated only in humans. Previously, Dr. Polleux discovered that human-specific duplicates of SRGAP2 help boost the number of connections, or synapses, that neurons form and make those synapses very slow to mature, two hallmarks that make human neurons unique among all mammals. This leads to neurons that have stronger and denser connections to their neighbors and are therefore better able to process and store information.
In the new study, Dr. Diaz-Salazar first discovered that human-specific duplicates of SRGAP2 are 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.
Previous research over the past 20 years or so has discovered that microglia, which make up 5 to 10 percent of brain cells, not only fight infections or help repair damage, but during development, they also help neurons decide which synapses they keep and which they discard. They can also increase or decrease how responsive synapses are in brain circuits.
In the new study, experiments with mice and with human cells revealed human-specific duplicates of SRGAP2 cause human microglia to take four to eight years to mature. In contrast, mouse microglia take about three weeks to mature.
“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.
The human brain is unique among mammals for how long it takes to mature. This prolonged development, known as neoteny, is thought to underlie humans’ advanced brainpower. The researchers now want to understand the precise mechanisms through which SRGAP2 promotes neoteny in neurons, microglia and other cells in 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.”
Key Questions Answered:
A: Microglia are the primary immune cells of the brain, making up 5 to 10 percent of brain cells. In addition to defending against infection and clearing damaged cells, they shape developing neural circuits by selecting which synapses to prune or keep and calibrating circuit responsiveness.
A: Neoteny refers to a prolonged rate of physiological development. Human-specific duplicates of the SRGAP2 gene slow down the maturation rate of both neurons and microglia, extending human brain development across years rather than weeks.
A: Neurons form dense connections that take years to finalize. Because microglia manage synaptic pruning and circuit refinement, their maturation must be synchronized with neurons to ensure precision shaping of complex human neural networks.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neurotech and memory research news
Author: Charles Choi
Source: Zuckerman Institute
Contact: Charles Choi – Zuckerman Institute
Image: The image is credited to Neuroscience News
Original Research: The findings will appear in Neuron
