A study in Neuron found that unique copies of SRGAP2 slow down and coordinate the maturation of microglia and synapses. The extended developmental window may allow for the formation of more complex neural networks, but the study did not directly test intelligence.
Mouse brain immune cells reach key stages of maturation in just a few weeks. Their counterparts in the human brain continue to develop for years. New study suggests a genetic mechanism that may help explain the difference: human-unique copies of the gene SRGAP2 Slows down the development of cellsMicroglia And coordinate it with the prolonged maturation rate of the connections between nerve cells.
The study, published in the journal Neuron, does not show that a single gene “created human intelligence.” It provides evidence that genetic duplications that occurred during human evolution contributed to extending the window of time during which microglia and neurons together shape brain circuits.
Immune cells that also shape the brain
Microglia are the resident immune cells of the central nervous system. They respond to infections and injuries, removing damaged cells and cell debris, and constantly scanning their environment.
In recent decades, it has become clear that their role is not limited to protection and cleaning. During Brain development They participate in the design of neural networks: they influence the creation ofsynapses – the communication points between neurons – and help determine which connections will be maintained and which will be eliminated. Microglia make up about five to ten percent of brain cells, so the rate of their maturation may have a broad impact on the development of neural circuits.
The human brain is characterized by an exceptionally long period of development. This phenomenon is called Neotenia – Prolongation of juvenile developmental stages compared to other species. This extended period may allow the brain to continue to change in response to learning and the environment for many years.
A gene family unique to a person
Frank Polo's lab at Columbia University has been studying the SRGAP2 gene family for more than 15 years. The ancient gene SRGAP2A is also present in other species, but during the evolution of the human lineage, several copies of it were created, including SRGAP2B and-SRGAP2C.
These copies are not complete copies of the original gene. They produce truncated proteins that reduce the amount of protein produced by SRGAP2A and alter its activity.
Previous studies by the group have shown that human copies of SRGAP2 slow down the maturation of synapses in neurons and ultimately increase the number of connections they form. A higher density of connections may increase the ability of neurons to process and store information, but it does not by itself mean higher intelligence.
In the new study, Carlos Diaz-Salazar, the first author of the paper, found that human copies of SRGAP2 are also highly active in microglia—almost ten times more so than in neurons, the researchers said. The finding raised the possibility that the gene family's influence is not limited to the neurons themselves.
Years in a human versus weeks in a mouse
The researchers compared the development of microglia in the cerebral cortex of humans and mice according to cell structure, gene expression, and functional indices.
It turned out that the maturation pathway of human microglia is much longer. In mice, the structural complexity of the cells reaches its peak about three weeks after birth, while in humans the corresponding peak appears around the age of seven. Various measures of human maturation continue to change for several years and even close to a decade.
The researchers didn't stop at comparing tissues. They created microglia from induced human stem cells and implanted them into mouse brains. Even within the mouse brain environment, the human cells maintained, at least in some respects, their slow rate of development. This suggests that part of the developmental "clock" is within the cells themselves and is not dictated solely by the brain's environment.
However, not all developmental features were preserved in the same way. The activity of markers related to the breakdown of material within the cell was influenced to a greater extent by the mouse environment. Thus, the rate of maturation is the result of a combination of the cell's internal program and the signals it receives from neighboring cells and tissues.
SRGAP2 modification altered the rate of maturation
To test whether the SRGAP2 family actually causes the slowdown and is not just associated with it, the researchers performed gene addition and deletion experiments.
Activation of human SRGAP2C in mouse microglia caused them to develop structural features associated with a prolonged maturation pathway. Conversely, reduction of SRGAP2B and SRGAP2C activity in human microglia altered their structural complexity.
The researchers conclude that the human copies reduce SRGAP2A activity, thereby slowing the rate of structural maturation of microglia. In experiments on mice, they also found that the SRGAP2 mutation in microglia affected the rate of development of dendritic spines – tiny extensions on which many synapses are formed.
The results indicate coordination between two developmental clocks: that of microglia and that of synapses. When microglia maturation was delayed, the development of neural connections was also delayed.
Coordination, not the "gen of intelligence"
The possible implication is that during human evolution, SRGAP2B and SRGAP2C acted simultaneously in two cell types: they slowed the maturation of neurons and the maturation of microglia that help shape their connections. This allowed the two cell types to remain coordinated throughout the long period of human brain development.
A long developmental window may allow for more connections to be made and for them to be adapted over time to experience and the environment. This is one possible mechanism that could have contributed to the emergence of unique features of the human brain, but the study did not examine intelligence, language, memory, or human behavior.
The authors of the article emphasize that many other factors may participate in the slow development of the human brain, including epigenetic mechanisms, cellular metabolism, changes in genetic control regions, different RNA splicing, and differences in the lifespan of proteins.
Limitations of the study
A key part of the experiments was conducted with human microglial cells transplanted into mouse brains. This is a model that allows human cells to be studied inside a living brain, but the environment surrounding them is still murine and does not fully replicate the interactions with neurons, astrocytes, immune cells, and gut bacteria in the human body.
The experiment in which SRGAP2B and SRGAP2C activity was reduced in human cells was also tested at a single key time point. The results are consistent with a change in the rate of maturation, but the researchers cannot completely rule out the possibility that the genes affect the overall complexity of microglial cells and not just their timing.
In addition, the precise molecular mechanism by which SRGAP2 alters microglial structure is still unknown. The results therefore provide a possible and compelling mechanism for coordinating development, but not a complete explanation for the evolution of the human brain.
The researchers plan to examine how the SRGAP2 family affects other brain cells and the microglia's response to disease. The study also found gene expression patterns that appear in microglia from Alzheimer's patients, but at this stage there is no proof of a causal relationship or a suggestion for treatment.
Questions and Answers
What are microglial cells? These are the resident immune cells of the brain and central nervous system. In addition to protecting against infections and eliminating damaged cells, they help form, strengthen, and eliminate connections between nerve cells.
What is special about the SRGAP2B and SRGAP2C genes? These are copies created by duplication of the ancient SRGAP2A gene in the human lineage. They produce truncated proteins that reduce the activity of the original protein.
How was the influence of genes tested? The researchers combined a comparison of human and mouse tissues, transplantation of microglial cells derived from human stem cells into mouse brains, and genetic models in which copies of SRGAP2 were removed or activated.
Has the study discovered the "human intelligence gene"? No. The study suggests a mechanism that may coordinate the rate of maturation of microglia and synapses. Cognitive abilities arise from multiple genetic, cellular, developmental, and environmental systems.
More on the subject on the science website
- Research in Nature: Not only neurons, but also astrocytes in the brain create a hidden communication network
- To mimic a single human neuron requires a deep neural network
- When the brain recruits the immune system: The connection between motivation, infections and cancer
- The human body is not a perfect machine: this is how evolution improvised solutions that work well enough
- Did the brain drive the Cambrian explosion?
