What makes microglia so interesting?
Glad you asked! Microglia are brain-resident immune cells. One of the many things that makes them special is that, under normal conditions, the brain and the spinal cord are closed off from the immune system. Thus, whereas the rest of our body has many innate and adaptive immune mechanisms for protection, microglia are the primary first responders and defense cells of the brain. Another fascinating aspect of microglia is that they perform a wide range of functions for the normal development and well-being of the brain. They clear cellular debris, prune synapses, modulate myelination, stimulate the formation of neurons, and eliminate excessive cells. Thus, microglia can sense a broad range of environmental cues and mount appropriate, context-dependent responses.
Microglia sound awesome! Do I hear a “but”?
…but, during aging and in neurodegenerative disorders, microglia display impaired phagocytic clearance, reduced motility, and aberrant activation to insults. For example, in Alzheimer’s disease, the chronic activation of inflammatory pathways by microglia leads to the indiscriminate loss of viable neurons and functional synapses, which in turn results in cognitive and motor deficits. Similarly, microglia may also contribute to the pathophysiology of neurodevelopmental and neuropsychiatric disorders. We are still learning the cellular and molecular mechanisms using which microglia both protect the central nervous system and can simultaneously turn against it in some individuals and under certain contexts.
Aren’t microglia just macrophages with a fancy name?
No! Although microglia are indeed brain-resident macrophages and professional phagocytic cells, they are morphologically, functionally, and transcriptionally distinct from other macrophages and monocytes. It is widely accepted that their origin, developmental trajectory, and brain-specific niche together confer microglia with a unique identity that cannot be recaptured by monocytes or other tissue-resident macrophages. Moreover, peripheral monocytes engrafted in the brain fail to acquire microglia-specific gene signatures, and microglia cultured in vitro rapidly lose their identity and show altered expression of many genes, particularly disease-associated genes. Therefore, it appears that examining microglia in their in vivo milieu is crucial for understanding their biology.
Why do you use zebrafish to study microglia?
Well, other than the fact that we think zebrafish are simply the best, there are many practical reasons zebrafish are well-suited to ask fundamental questions about microglia biology and function. Zebrafish embryos are optically transparent, allowing us to visualize the distinct steps of the development of microglia, and the neuroimmune system, using live, in vivo imaging. Zebrafish also produce a large number of eggs, and we can use their fecundity to perform functional genetic screens of genes implicated in neurodegenerative, neurodevelopmental, and neuropsychiatric disorders. These experimental advantages of zebrafish allow us to make key insights into microglia biology that would likely be inaccessible in other model systems.