What's the buzz: Microglia

There is growing evidence demonstrating that immune cells and signaling molecules serve as carriers in an intricate network of bidirectional communication between the immune system and the brain. This occurs via peripheral immune pathways as well as through interactions between neurons and the resident immune cells in the brain known as microglia. It turns out that microglia are involved in a lot more than just protecting the brain from infections; it has been shown that microglia are capable of influencing the growth and activity of neighbouring neurons. This affects the plastic nature of neuronal networks, and thus microglia are able to affect cognitive and social behaviors. 

In a recent study from Jonathan Kipnis' lab at University of Virginia, School of Medicine, researchers showed that restoring microglial function in a mouse model of Rett Syndrome, a severe autism-spectrum disorder that affects 1 in 10,000-20,000 girls worldwide. The disease is caused by a mutation in the gene MECP2, which is carried on the X chromosome. Since males carry only one copy of the X chromosome, males with the mutation die very soon after being born, whereas girls with one copy of the mutation develop the disease. 

Signs of the disease typically set in between 6 and 18 months of age. Affected females often have trouble developing speech, walking and putting on weight. Many patients also develop breathing problems and apnoeas. They also display repeated behaviors such as hand washing and wringing. 

MECP2 is an important epigenetic regulator, meaning it is able to regulate the expression of genes by recruiting enzymes that modify the structure of chromatin network. How exactly a mutation in the gene is sufficient to cause Rett Syndrome is still a mystery, but researchers have been able to detect its expression widely in the brain. In fact, rescuing MECP2 expression in neurons in Rett Syndrome mice reverses some of the disease phenotypes. More recently however, researchers lie Kipnis began to look for MECP2 function in other cell types in the brain, like microglia. It is now known that microglia indeed do express MECP2, so Kipnis and colleagues began to ask whether restoring MECP2 function in microglia in a Rett Syndrome mouse would improve the symptoms. 

The researchers accomplished this by essentially replacing the immune system of the mutant mouse lacking MECP2. They first had to kill of the existing immune system using radiation, and then used a bone marrow transplant from a healthy wildtype mouse to the mutant mouse; thus the new microglia in the Rett Syndrome mouse now have MECP2 in them. In an unexpected result, the restoration of MECP2 function in microglia resulted in drastic improvements in the mutant mice; they began to breathe and walk better, and even gain weight more easily compared to the non-transplanted mutant mice. 

These findings, while exciting, are very preliminary in terms of bone marrow transplants being used in human Rett Syndrome patients.  At this point, Kipnis speculates that their results could be explained by the fact that microglia in mutant Rett Syndrome animals are unable to clear up and protect the neurons from cellular waste build up and potential pathogens, and thus neuronal function is impaired. More research is required to identify the mechanism of microglia function in Rett Syndrome. However, the study does provide a novel role for microglia in the brain, and a new target for treatment of Rett Syndrome.