You may have heard these amazing numbers before: “Our brain contains 100 billion neurons and 10 times as many glial cells.”
Well, more like 86 billion neurons and about as many glial cells, argues Suzana Herculano-Houzel in her articles and TED talks. 1
While this relatively recent controversy in neuroscience may make the subject of another article in itself, today we’ll take a closer look at those glial cells – specifically, astrocytes. Regardless of their exact number, they certainly play a crucial role in everything the brain does.
As such, we’ll take a look at:
- What are astrocytes?
- What do astrocytes do?
- Where do astrocytes come from?
- What happens when astrocytes don’t perform their role properly?
- Can we use astrocytes in treatments?
What are astrocytes?
Astrocytes are a type of glial cells.
While neurons are an exquisite piece of biological machinery, they do not perform all their fascinating functions on their own. A large number of the cells in the central nervous system are, in fact, support cells – the so-called glial cells. First noticed by Rudolf Virchow as far back as 1846, they were then described as a homogenous population that generally supports neurons. We now know they are anything but homogenous. 2
Various types and shapes of glial cells can be found throughout the nervous system. For example, if we take a closer look at the peripheral nerves, we may discover Schwann cells wrapping around the axons and producing their invaluable myelin sheath. In the central nervous system, we’ll instead find oligodendrocytes providing myelin to as many as 30 neurons at a time. Myelin then acts as insulating material, ensuring proper and incredibly fast transmission of information across the axon – more on this, perhaps, another time.
Another type of glial cells found in the central nervous system is known as microglia – tiny immune cells, somewhat related to macrophages, that try to defend the brain against infections or injury.
Astrocytes, a type of glial cell we find in the central nervous system alongside oligodendrocytes, get their name from their star-like cell body. With their numerous and long processes, they envelop blood vessels throughout the brain or wrap around neuron cell bodies and synapses.3
What do astrocytes do?
Their exact and full roles remain yet to be elucidated. While the other glial cells we discussed have a clear function, such as modulating signal transmission or immune protection, astrocytes are currently thought to support neurons through other means: 2,3
- Taking part in the blood-brain barrier
- Providing a scaffold for the nervous system, as well as separating neurons, thus insulating synapses from each other
- Helping regulate K+ in the extracellular fluid
- Recovering neurotransmitters from a synapse after they’ve elicited their signal
- Nourishing nearby neurons
A non-negligible role of astrocytes resides in their response to injury – the so-called glial scar, or reactive astrogliosis. When the brain or spinal cord are injured (by, for example, a stroke), astrocytes respond by dividing and accumulating on site. Subsequently, they surround the damaged area and isolate it with a think scar-like tissue.
Scientists have realized that this glial scar is not an ordinary, stereotyped process that just covers any injury, but rather a sophisticated switch that depends on the context, severity and nature of the damage.4
Nevertheless, excessive attempts at protecting the brain can, ultimately, prove non-beneficial. Such is the case of Alzheimer’s disease, for example – where astrocytes are thought to be beneficial in the initial, asymptomatic stages of the disease by internalizing the excess amyloid plaques in the brain, while, in later stages, the extreme stress they are under proves cytotoxic and, ultimately, toxic to the neurons as well. 5
Where do astrocytes come from?
Interestingly enough, glial cells come from the same kind of stem cells as neurons. These stem cells, called radial glial cells, first give rise to neurons, after which they switch their allegiance and start producing glial cells. The new-born glial cells then migrate away from the site they emerged until they occupy the entire nervous system. Once they’ve arrived in their new location, they become all grown-up and responsibly take on whichever function they were designed to do.2
And designed they seem to be, indeed. It appears that astrocytes are not a homogenous population of cells in themselves, either. In fact, there are two main types of astrocytes that researchers prefer to use when describing them:
- Fibrous astrocytes reside in the white matter
- Protoplasmic astrocytes reside in the gray matter
More recent work describes two more distinct morphologies – the interlaminar astrocytes (found in the 1st cortical layer) and varicose projection astrocytes (found in layers 5 and 6). These two subtypes in particular have, so far, only been observed in the human and primate brain.5
Not only this, but astrocytes may accommodate their functions to the region they are in, such that minute differences may be found between an astrocyte in the brain stem and one in the temporal lobe, for example. Researchers have, indeed, found that astrocytes residing in the brainstem, in the vicinity of respiratory centers, are highly sensitive to changes in pH and release ATP to promote respiratory drive. 2,5
What happens when astrocytes don’t perform their role properly?
Having such a diverse set of roles, it stands to reason that when astrocytes lose their function the brain as a whole suffers. Astrocyte dysfunction has been associated with a number of diseases ranging from genetic syndromes to neurodegeneration and even psychiatry (e.g., genetic models of autism, multiple sclerosis, Alzheimer’s disease, Huntington’s disease). 2
There is, in fact, a rare neurodegenerative disease that is thought to be exclusively driven by astrocyte dysfunction.
Alexander’s disease is a genetically-acquired neurodegenerative disease that affects young children, often before the age of 2. The young patients usually have a larger-than-average head (and brain), may experience seizures or stiffness in their arms and legs, and will likely not hit the developmental milestones in the same way as their peers. Unfortunately, the prognosis of the disease is poor, with many children not surviving past the age of 6.5,6,7
The cause of the disease has been identified as an inherited mutation in GFAP – a protein that makes up the skeleton of glial cells, astrocytes in particular. What scientists noticed when examining the brain of such patients was a colorful accumulation of this abnormal protein in astrocytes, which got the name of Rosenthal fibers.
The first documented case is that of Alexander, in 1949 – a 16-year-old boy who passed away due to the disease. Since then, only about 500 cases have been recorded worldwide, although due to difficulties in diagnosis, this estimate may be inaccurate. Despite researcher’s efforts, no life-changing treatment has been found as of yet, and doctors are left to manage symptoms as they come along. 8
Can we use astrocytes in treatments?
Seeing how astrocytes seem to hold such a large number of beneficial roles for the central nervous system and be implicated in several diseases, we may think it is time to harness their power in treatments. But can we actually do that?
In short, not yet, as it is quite a challenging endeavor. Several limitations need to be overcome first, such as designing a strategy to properly traverse the blood/brain barrier or designing a drug so specific that it only targets astrocytes and nothing else.
Several directions are being explored at the moment, notably gene therapy – with the aim of modulating astrocyte-specific signaling pathways or nanotechnology – providing a way of sending drugs across the blood/brain barrier such that they actually reach the astrocytes. Another interesting prospect is that of cell replacement therapy – transplanting healthy astrocytes to the central nervous system, in hopes of reverting the hostile microenvironment created in a diseased brain.
A Phase I clinical trial attempted using this treatment on ALS patients and got promising results, apparently increasing the survival of patients’ motor neurons. This raised hope for other diseases, such as Parkinson’s, for which animal studies are underway. 4
Summing up, astrocytes are a truly remarkable supporting feature of our nervous systems – dynamic, willing to adapt to the local requirements and to perform a vast (and not yet fully understood) array of functions. Elucidating as much of the mystery that still seems to surround them will undoubtedly bring us closer to understanding the complexity of the human brain.
Resources:
- Azevedo, F. A. C. et al. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J. Comp. Neurol. 513, 532–541 (2009).
- Molofsky, A. V. & Deneen, B. Astrocyte development: A Guide for the Perplexed. GLIA 63, 1320–1329 (2015).
- Kandel, E., Schwartz, J., Jessell, T., Siegelbaum, S. & Hudspeth, A. J. Principles of Neural Science. (Elsevier, 2012).
- Valori, C. F., Guidotti, G., Brambilla, L. & Rossi, D. Astrocytes: Emerging Therapeutic Targets in Neurological Disorders. Trends in Molecular Medicine 25, 750–759 (2019).
- de Majo, M., Koontz, M., Rowitch, D. & Ullian, E. M. An update on human astrocytes and their role in development and disease. Glia 68, 685–704 (2020).
- Alexander disease - Genetics Home Reference - NIH. Available at: link. (Accessed: 25th July 2020).
- Alexander Disease Information Page | National Institute of Neurological Disorders and Stroke. Available at: link. (Accessed: 25th July 2020).
- Messing, A., Brenner, M., Feany, M. B., Nedergaard, M. & Goldman, J. E. Alexander disease. J. Neurosci. 32, 5017–5023 (2012).
