Knowing Neurons
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Neuro Primer: Microglia

By Keionna Newton

Microglia structure and function

As you go about each and every day, there are billions – yes, billions – of tiny little cells in your brain moving around busily, working hard to keep your brain health in check. These cells never truly rest, constantly extending and retracting their beautifully branched arms, monitoring their local space for any first signs of potential threat to the delicate harmony of the brain’s environment. These tiny but mighty cells are known as microglia. “Glia” comes from the Latin word for “glue”, as it was long thought that microglia play a more passive role in the brain: simple scaffolding for all of the brain’s neurons to hold them together. Now, we know that microglia deserve a lot more of our respect as central players in brain function and disease. The discovery of microglia is credited to the Spanish neuroscientist Pio del Rio-Hortega. In 1919, he first identified these peculiar brain cells by the several branching structures coming from their tiny (hence, “micro”) cell bodies, an overall morphology which set them apart from neurons and other glial cells such as astrocytes (Umpierre et al., 2020). 

when microglia detect harmful invading organisms (such as certain bacteria), their defense mechanisms become activated and they unleash a whole host of mechanisms that few pathogens can withstand

These finely branched protrusions are known as the microglia’s processes. Almost like arms, they reach out over long distances to grab debris or dead cells, engulfing the material and cleaning up the environment (Colonna et al., 2017). As the resident immune cells of the brain, microglia also actively combat pathogens. In the healthy brain, microglia have small cell bodies, significantly branched processes, and only monitor the immediate environment that they reside in. However, when microglia detect harmful invading organisms (such as certain bacteria), their defense mechanisms become activated and they unleash a whole host of mechanisms that few pathogens can withstand. Under these contexts, microglia undergo specific shape changes, becoming less finely branched and more bushy in appearance, in addition to increasing the size of their cell bodies (Lier et al., 2021). These changes in shape aid in their ability to “phagocytose” – or “eat” – and degrade the disease-causing material, an important feature observed in many diseases. Microglia also undergo changes in gene expression and will release proinflammatory proteins known as cytokines to signal to other cells that something is wrong, thus recruiting help and activating the immune response (Colonna et al., 2017). 

Diversity of microglia throughout the brain

On top of these well-established microglia functions, recent discoveries in the field suggested that microglia are vastly heterogeneous throughout the brain, raising questions about the primary functions of these cells. From studies conducted in mice, researchers demonstrated that microglia display differences in cellular density, morphology, gene expression, metabolism, and even motility (the ability to move on their own – a hallmark of microglia) depending on which brain region you are looking at (De Biase et al., 2017; Stowell et al., 2018; Jurga et al., 2020). Even more intriguing, these changes in microglial make-up appear to be highly specific to their local environment, with microglia populations exhibiting striking differences even in brain regions that reside extremely close to one another (De Biase et al., 2017). The reasons why microglia exhibit these brain region specificities remain elusive and are among the great mysteries that researchers are currently tackling in attempts to unravel the full picture of microglial function. 

microglia display differences in cellular density, morphology, gene expression, metabolism, and even motility (the ability to move on their own – a hallmark of microglia) depending on which brain region you are looking at

Microglia as key players in neurodevelopment

Microglia truly are the full package. Apart from their role in regulating immunity, microglia also sculpt neuronal circuitry during brain development. Without them, things can go drastically wrong in the initial stages of building a brain. In a recent study conducted by Dr. Adam Denes from the Institute of Experimental Medicine, researchers found that during early development microglia extend their processes to make contact with highly specialized sites on the cell bodies of immature neurons (Cserép et al., 2022). The authors proposed this as a mechanism used by microglia to monitor the status of immature neurons and exert control over their development. When the researchers deleted the microglial receptors responsible for this contact, known as P2RY12, it led to abnormal neurodevelopment of the cortex that lasted into adulthood. This is particularly consequential, as the cortex is responsible for higher-level brain functions including language, sensory processing, thinking, emotions, consciousness, and even your personality (Jawabri & Sharma, 2023). 

Additionally, microglia are crucial drivers for the remodeling of synapses during early development. During development, the brain contains many more synapses than it will end up with in adulthood. This is where microglia shine, as they engulf – or “prune” – synaptic inputs and can also induce the formation of new filopodia: protrusions from cells which almost act as “antennae” for probing the environment (Mattila & Lappalainen, 2008). Filopodia can then lead to the development of new dendritic spines, specialized protrusions on neurons thought to be highly important for functions such as learning and memory (Schafer et al., 2012; Weinhard et al., 2018; Runge et al., 2020). 

Roles for microglia in adulthood

Microglia also contact specialized sites on neuronal cell bodies in adulthood. They appear to be an important way for microglia to communicate with neurons, allowing them to monitor neuronal status and protect the integrity of neuronal function and connectivity after brain injury (Cserép, 2020). Microglia also play important roles in modulating neuronal activity and synaptic plasticity in the mature brain. Research conducted in mice has revealed that microglia respond to highly active synapses, contacting them with their processes and subsequently suppressing the excessive neuronal activity, effectively quieting the overactive synapses (Badimon et al., 2020). The researchers proposed that this mechanism may serve as a neuroprotective factor to prevent aberrant neuronal activity patterns, such as those observed in conditions like epilepsy.  

Microglia also play important roles in modulating neuronal activity and synaptic plasticity in the mature brain

Additionally, neuronal activity seems to directly influence the motility of microglia. Researchers from the German Center for Neurodegenerative Diseases demonstrated a correlation between neuronal activity and the rate of microglial contact with dendritic spines on CA1 neurons in the hippocampus of mice, a brain region vital for learning and memory (Nebeling et al., 2022). Interestingly, this rate of contact was associated with their stability, removal, or formation of new spines. As you might imagine, these changes in spine density implicate microglia as active participants in neural circuitry rewiring, even into adulthood. Currently, researchers believe that these microglial-neuronal interactions have direct implications for all sorts of cognitive functions and behaviors, both in health and disease.

Microglia in neurodegeneration

While you can definitely thank microglia for all the hard work they do to keep the brain healthy and functioning properly on a daily basis, some emerging studies also hint at a darker side to microglia. These tiny cells are helpful to the brain in most instances (otherwise evolution wouldn’t have bothered to keep them around!), but they aren’t perfect, especially when it comes to aging and neurodegenerative disease where you sometimes see a breakdown in their beneficial capacities. Recent evidence from human GWAS studies describes more than 20 genes associated with Alzheimer’s disease (AD) risk, many of which are predominantly expressed in microglia  (Efthymiou et al., 2017; Villegas-Llerena et al., 2016). 

These tiny cells are helpful to the brain in most instances (otherwise evolution wouldn’t have bothered to keep them around!), but they aren’t perfect, especially when it comes to aging and neurodegenerative disease where you sometimes see a breakdown in their beneficial capacities

In AD, for currently unknown reasons, the beneficial functions of microglia such as phagocytosis can go haywire. Microglial pathways that are responsible for pruning synapses in early development appear to be inappropriately activated, leading to excessive pruning of synapses by microglia and thus significant detrimental synapse loss and cognitive impairment, which are both hallmarks of AD pathology and dementia more generally (Hong et al., 2016; Stephan et al., 2012). Microglia-associated deleterious mechanisms have also been identified in several other neurodegenerative diseases including Parkinson’s disease, a pathology characterized by progressive loss of dopamine neurons which are important for reward processing, movement, and cognition (Salter et al., 2017). However, the field still hotly debates the spectrum on which these microglial mechanisms in disease are neuroprotective or neurotoxic. 

All of the things you’ve just learned about microglia are only the tip of the iceberg. There are so many more unanswered questions about these diverse cells that are only just beginning to be investigated. Perhaps one day you might even join the exciting research efforts to unravel all the many mysteries of microglia!

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Written by Keionna Newton
Illustrated by Sneha Chaturvedi
Edited by Lauren Wagner, Rebeka Popovic, & Gabrielle Sarlo

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microglia in purple against a black background, pink microglia pictured around the M, in the O, and as part of the A in the word microglia

References

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Colonna, M., & Butovsky, O. (2017). Microglia function in the central nervous system during health and neurodegeneration. Annual Review of Immunology, 35(1), 441–468. 

Cserép, C., Schwarcz, A. D., Pósfai, B., László, Z. I., Kellermayer, A., Környei, Z., Kisfali, M., Nyerges, M., Lele, Z., Katona, I., & Ádám Dénes. (2022). Microglial control of neuronal development via somatic purinergic junctions. Cell Reports, 40(12), 111369. 

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Mattila, P. K., & Lappalainen, P. (2008). Filopodia: Molecular Architecture and cellular functions. Nature Reviews Molecular Cell Biology, 9(6), 446–454. 

Nebeling, F. C., Poll, S., Justus, L. C., Steffen, J., Keppler, K., Mittag, M., & Fuhrmann, M. (2022). Microglial Motility Is Modulated by Neuronal Activity and Correlates with Dendritic Spine Plasticity in the Hippocampus of Awake Mice. eLife 

Runge, K., Cardoso, C., & de Chevigny, A. (2020). Dendritic spine plasticity: Function and mechanisms. Frontiers in Synaptic Neuroscience, 12

Salter, M. W., & Stevens, B. (2017). Microglia emerge as central players in brain disease. Nature Medicine, 23(9), 1018–1027. 

Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012). Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron, 74(4), 691–705. 

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Author

  • Keionna Newton

    Keionna is currently pursuing her PhD in Neuroscience in the lab of Dr. Lindsay De Biase at UCLA. She graduated from the University of Washington in 2021 where she used mouse models to investigate the cellular and molecular mechanisms of stress, pain, and addiction, with particular focus on kappa opioid receptors. Now at UCLA, Keionna’s research is focused on understanding how microglia modulate dopamine neuron circuitry in health and disease. Outside of the lab, Keionna enjoys hiking, backpacking, painting, reading books, and playing her guitar.

Keionna Newton

Keionna is currently pursuing her PhD in Neuroscience in the lab of Dr. Lindsay De Biase at UCLA. She graduated from the University of Washington in 2021 where she used mouse models to investigate the cellular and molecular mechanisms of stress, pain, and addiction, with particular focus on kappa opioid receptors. Now at UCLA, Keionna’s research is focused on understanding how microglia modulate dopamine neuron circuitry in health and disease. Outside of the lab, Keionna enjoys hiking, backpacking, painting, reading books, and playing her guitar.