By Melanie Das
We all know that microglia respond to damage, clear up pathogens, toxic proteins and debris. However, Dr. Beth Stevens wants you to know that microglia are so much more than that. Microglia are dynamic cells that continuously survey the healthy brain. So what do microglia do in their spare time? At the Presidential Lecture titled “Immune Mechanisms of Synapse Loss in Health and Disease”, during the Society for Neuroscience meeting in Chicago, Stevens presented her lab’s prolific work demonstrating the crucial role of microglia in shaping neural circuits. Microglia modulate synaptic connections through pruning. Too much or too little pruning can shift a healthy brain into an unhealthy state. Microglia-mediated synaptic pruning is essential to development and dysregulation of this process can potentially play a role in developmental and degenerative diseases.
The complement system is classically known to play a role in the immune system to tag unwanted cells or debris which are ultimately phagocytosed by macrophages. A novel role for this system is to tag synapses for elimination. In development, immature synapses can be targeted by the complement system and then eliminated by microglia, forming precise neuronal circuits.
Microglia and the complement cascade have both been suggested to play a role in psychiatric disorders like schizophrenia. Can aberrant synaptic pruning play a role in schizophrenia? To explore this question, the Stevens lab collaborated with the neighboring McCarroll lab at Harvard, who had identified a specific variant of the complement C4 gene, C4A that was correlated with increased risk of schizophrenia. This protein is part of the complement cascade required for tagging cells for elimination. Increased C4A may cause aberrant synaptic pruning. This work was fascinating because the identification of a genetic risk factor yielded a novel molecular mechanism behind a complex psychiatric disease. Hopefully, understanding this new role for microglia will also uncover novel ways in which synaptic pruning goes awry in many more diseases where there is known microglial contribution.
While microglia play a beneficial role in synaptic pruning during development, Stevens wondered whether ‘neurodevelopmental virtues become neurodegenerative vice?’ Synapse loss is one of the early hallmarks of nervous system aging and neurodegenerative diseases. Her team hypothesized that synapse loss in aging and Alzheimer’s disease (AD) is actually an aberrant reactivation of the same developmental mechanisms of synaptic pruning. In aging, they found that the complement system plays a role in aging and that knocking out C3 of the complement system protects against cognitive decline and synapse loss in aging mice. In another set of experiments, the group found that the complement system contributes to the early synapse loss in AD.
Microglia and inflammation have long been implicated as playing both beneficial and negative roles in neurodevelopmental, psychiatric and neurodegenerative diseases. Further understanding of this novel function of microglia means discovering new mechanisms that could contribute to various diseases. For therapeutic benefit, we may need to identify ways to modulate the complement cascade to ameliorate aberrant synaptic pruning.
If you have to take-away one message from this recap post, remember that even in your healthy, daily life microglia are constantly working away to maintain, preserve and fix the synaptic connections in your brain. So don’t forget to call up your microglia to thank them and tell them you love them!
Any views expressed are those of the author, and do not necessarily reflect those of PLOS.