What do glial cells do in the brain

Satellite glia provide nutrients and structural support for neurons in the PNS. Microglia scavenge and degrade dead cells and protect the brain from invading microorganisms. Oligodendrocytes , shown in Figure 2b form myelin sheaths around axons in the CNS.

One axon can be myelinated by several oligodendrocytes, and one oligodendrocyte can provide myelin for multiple neurons. This is distinctive from the PNS where a single Schwann cell provides myelin for only one axon as the entire Schwann cell surrounds the axon. Radial glia serve as scaffolds for developing neurons as they migrate to their end destinations.

Ependymal cells line fluid-filled ventricles of the brain and the central canal of the spinal cord. They are involved in the production of cerebrospinal fluid, which serves as a cushion for the brain, moves the fluid between the spinal cord and the brain, and is a component of the choroid plexus.

Figure 2. Moreover, astrocytes might play different roles in diverse pathological conditions. Along the same line, no effect could be found on disease onset, duration, neuronal loss or motor function in astrocyte ablated mice for two different models of neurodegenerative diseases injection of the neuroadapted Sindbis virus NSV inducing neuronal death as well as in a genetic model of ALS Lepore et al. However, the number of proliferating astrocytes in these neurodegenerative disease models is relatively low in comparison to the other models of pathology.

These contradictory results might simply be an effect of low numbers of ablated astrocytes and more remaining ones that are able to react, rather than of their function. In summary, the ablation of astrocytes under pathological conditions has given a clear functional readout for the first time: astrocytes play a crucial role in the maintenance of the diseased tissue and in the inhibition of secondary tissue damage by blocking inflammation Figure 2 ; Table 2.

This interpretation has to be taken with care, as only proliferating astrocytes were ablated in all the approaches described above, while the non-proliferating cells retained normal function that might be different or even opposing to that of the proliferating ones. Moreover, it is now textbook knowledge that although scar forming astrocytes are beneficial to injury, they also have detrimental effects on tissue regeneration Pekny and Pekna, ; Sofroniew, These aspects were only slightly addressed in the experiments mentioned above, giving space for further ablation approaches in the future.

Although NG2-glia are precursors of mature oligodendrocytes within the oligodendrocyte lineage, they are often considered an independent glial population due to their additional characteristics. In relation to the long history of neuroscience, NG2-glia are a relatively young cell type in terms of discovery with identification only 30 years ago ffrench-Constant and Raff, Although a great amount of work has been performed on these cells, the cellular function of NG2-glia — at least in the adult brain — remains largely a mystery.

However, many cellular characteristics have been described: NG2-glia are part of the oligodendrocyte lineage and keep generating mature myelinating oligodendrocytes throughout lifetime Dimou et al.

Most interestingly NG2-glia in the adult rodent brain form a tight homeostatic network in which the cell numbers are maintained under physiological conditions. As soon as one cell has been lost due to either differentiation or cell death, the remaining gap is immediately replaced by a neighboring cell Hughes et al. Furthermore, NG2-glia are the only highly proliferative cells in the brain parenchyma Dimou et al.

The most curious aspect of NG2-glia is their ability to form functional synapses with neurons, originally discovered in the hippocampus Bergles et al. The function of these synapses is not well understood. One interesting aspect of these synapses is the directionality, as NG2-glia are only able to receive neuronal signals but cannot create action potentials on their own and propagate them further De Biase et al.

The ablation approaches that are discussed in this section give some insight in the role s of NG2-glia in the adult brain. Further on in the lineage, the function of mature oligodendrocytes is clear: they are the myelin-producing cells that insulate axons to allow a rapid saltatory conduction and give trophic support to axons reviewed in Nave, But as high numbers of presumably non-myelinating oligodendrocytes are also present in sparsely myelinated brain regions like the gray matter of the cerebral cortex, some functional aspects may have been overlooked.

To address this question, specific oligodendrocyte ablation approaches may deepen our understanding of the functions of these cells. Although NG2-glia were only discovered a short time ago ffrench-Constant and Raff, , several approaches to deplete these cells from the adult brain have already been developed. As NG2-glia are well characterized on the cellular level, these approaches mainly aimed to clarify the physiological function of these cells.

However, most of these approaches have been rather disappointing until recently, both in terms of achieving a NG2-glia-free brain as well as in identifying the physiological function of these cells.

The ablation of NG2-glia proved to be more difficult in comparison with other glial cell populations: due to their tightly regulated homeostasis Hughes et al. So far no method has successfully ablated all NG2-glia over a long period of time, as can be achieved successfully for microglia compare Table 3 and Figure 3.

Although technically quite different, all of the ablation approaches for NG2-glia commonly demonstrated the highly efficient repopulation capacity of resident NG2-glia, ranging from two to 6 weeks depending on the study. Two-photon in vivo imaging demonstrated the mechanism by which these cells become aware of their need for proliferation: they are able to sense cell-free gaps with their fine filopodia, triggering their migration or proliferation in order to fill the gap Hughes et al. Interestingly, these repopulating cells seem to be less branched and occupy a smaller surface area Birey and Aguirre, However, this could change over time as the cells re-grow and re-gain their original cellular complexity.

TABLE 3. NG2-glia ablation and differentiation block approaches under healthy conditions. Effects and dynamics of NG2-glia ablation under healthy conditions. The very efficient repopulation occurred either immediately or between 2 and 6 weeks after the ablation, depending on the study.

Although the function of NG2-glia has long been a mystery, recent studies showed that the NG2-glia ablation negatively affects the leptin-dependent energy metabolism and leads to a depression like behavior. Although the repopulation capacity of NG2-glia — independent of the ablation approach — has fundamentally proven to be fast, it declines with aging Chari et al. In correlation with their slowing physiological cycling behavior, the cell cycle length increases with aging Psachoulia et al.

Early studies depleting NG2-glia both in the spinal cord as well as in the brain with high-dose X-irradiation demonstrated an efficient repopulation within four to 6 weeks following the ablation treatment Chari and Blakemore, ; Irvine and Blakemore, The nature of these regional differences might either lie in a different cell cycle length of NG2-glia, as X-irradiation mainly affects fast cycling cells, or it may be an issue of different developmental origins or regional heterogeneity of those cells Kessaris et al.

The use of a single cell type-specific antibody to estimate the efficiency of depletion can lead to an overestimation since some proteins might be down-regulated upon a change in brain homeostasis, as shown for neurons after injury Pignataro et al. If this also holds true for NG2-glia, the X-irradiation method would solely lead to a failure to detect these cells with the use of an anti-NG2 antibody although they are still present.

NG2-glia are known to be the only proliferating cells outside the neurogenic niches in the healthy adult brain and therefore suspected to be the only cell type responding to X-irradiation. However, after a mild irradiation injury, other cells like microglia and astrocytes become reactive upon any cellular death, potentially triggering their proliferation in response to damage. This would make them sensitive to irradiation-induced cellular death, hence weakening the cell type specificity of this method.

A more specific and therefore more elegant way to follow the dynamics of ablation and repopulation of NG2-glia in vivo by overcoming the pitfalls of detection with different antibodies, is the use of genetically modified mouse lines to intrinsically label NG2-glia. As this tamoxifen-inducible marker is permanently expressed under the ubiquitous Rosapromoter, the downregulation of this locus is very unlikely to happen. Combining this mouse line with the intraventricular administration of AraC, a toxic agent interfering with the cellular DNA synthesis and inducing cell death in fast cycling but not slow or non-cycling cells Doetsch et al.

This ablation was then followed by a subsequent, complete repopulation within 2 weeks. Furthermore, with the use of BrdU-labeling experiments, insights were provided that the repopulation of NG2-glia exclusively occurs through proliferation of surviving adjacent NG2-glia located in an area without AraC diffusion, but not from a NG2-negative stem cell source.

These first ablation studies fundamentally characterized the repopulation capacity of NG2-glia, but did not answer the question about the NG2-glia function in the adult brain.

Two recently published NG2-glia ablation studies have so far directly addressed the functional outcome of an at least transient lack of NG2-glia Birey et al. Birey et al. This work therefore indicates that NG2-glia have a direct influence on the functionality and the properties of the neuronal network.

The mechanisms of this interaction still remains, however, a speculation. Djogo et al. In this work, it could be demonstrated that under physiological conditions NG2-glia in the hypothalamus contact dendritic processes of leptin receptor neurons which degenerate upon NG2-glia ablation, reducing leptin signaling. Hence, NG2-glia are essential to maintain the function of leptin receptor neurons in the hypothalamus, therefore proving for the first time a direct role for NG2-glia in the maintenance of the thalamic energy metabolism.

The need for these newly generated oligodendrocytes in the adulthood remains, however, not well understood. A recent study tested the hypothesis whether chronic NG2-glia ablation also influences the oligodendrocyte differentiation and assessed potential functional consequences Schneider et al.

This study took advantage of the above mentioned genetic ablation model in which the deletion of the cell cycle protein Esco2 driven by the Soxpromoter induces apoptosis of proliferating NG2-glia.

This depletion of recombined cells yielded a reduced oligodendrogenesis that further resulted in an elongation of the nodes of Ranvier, reduction of the saltatory nerve conduction as well as in motor dysfunctions, therefore demonstrating the importance of constant oligodendrogenesis in the adult brain.

In line with the above mentioned study, it could be demonstrated that the lifelong oligodendrogenesis is required for physiological function of the brain — in this case in the very early stages of complex motor skill learning. While the functional outcome of a NG2-glia ablation is just at the beginning of being understood, the role of oligodendrocytes and their ablation in the adult brain has been subjected to studies for several years compare Table 4 and Figure 4 , not only in the rodent CNS Vanderluit et al.

Furthermore, a broad variety of demyelination models that are used to study Multiple Sclerosis MS like, e. Effects and dynamics of oligodendrocyte ablation under healthy conditions. Very commonly, although very diverse in the use of promoters and suicide genes, these approaches induced oligodendrocyte death that in most cases resulted in primary demyelination followed by secondary induced neuronal damage.

These observations were in most cases accompanied by a behavioral phenotype resulting from demyelination. This phenotype could, however, take up to 50 weeks to appear, depending on the model. After a longer time, demyelination was followed by a spontaneous remyelination. Only one study observed axonal damage without global demyelination that could be due to the loss of trophic axonal support. Since oligodendrocytes do not have particular unique features like being proliferative, all of the used approaches are taking advantage of a toxin-induced ablation system amongst which the DTA-system is the most common one in combination with promoters that are specific for oligodendrocytes summarized in Table 4.

DTA toxicity in oligodendrocytes was, e. This was accompanied with the development of an autoimmune response against myelin Traka et al. Already some time ago, Vanderluit et al. This LacZ-system approach allows the focal ablation of cells that can even be controlled in size, while all the other described studies used systemic drug application and hence targeted and ablated oligodendrocytes in the complete CNS.

However, this study did not report any functional outcome of the ablation but might be a good tool for future experiments. Despite the differences in the ablation approach and possibly the functional readout, all studies have in common that the death of myelinating oligodendrocytes leads to a primary demyelination with a persisting secondary induced axonal damage and a subsequent spontaneous remyelination Figure 4.

In most of the studies the demyelination and the axonal damage are accompanied by severe motor dysfunctions like tremor, ataxia as well as weight loss or even the development of seizures. Although there is a severe loss of myelin and an accumulation of myelin debris, one study reported about the absence of the development of an autoimmune-response, what is generally thought to happen during MS pathology Locatelli et al.

Due to the widespread myelin loss, the biology of these models all together creates a perfect tool for studying remyelination besides analyzing the outcome of oligodendrocyte death. Interestingly, Oluich et al. In summary, the specific ablation of both NG2-glia as well as oligodendrocytes using different approaches proved to be similarly effective than for the other glial cell types; in case of the NG2-glia at least transiently as they repopulate very fast see Table 3.

While for the oligodendrocytes the functional outcome of myelin loss and axonal damage seemed to be quite foreseeable Table 4 , the role of NG2-glia in the adult brain remains open and further ablation studies could give a deeper insight. Many cellular characteristics of NG2-glia and their activation upon different pathologies have been well described.

Like astrocytes and microglia, NG2-glia were shown to react to various kinds of pathological insults, however, only when accompanied with an opening of the BBB Rhodes et al.

Two-photon in vivo imaging studies even revealed a very heterogeneous reaction of NG2-glia to injury: cell migration, proliferation, hypertrophy, and even combined reactions are possible Hughes et al. Moreover, it became clear that NG2-glia strongly increase in number and align around the lesion site as part of the glial scar Levine et al.

Besides these observations, the cellular role of NG2-glia under pathological conditions remains unresolved — comparable to the healthy brain.

Interestingly, unlike the other glial cell types, so far there are no published studies that specifically ablate NG2-glia under pathological conditions.

However, as the ablation approaches under healthy conditions are quite successful — at least transiently — they seem to be a very promising tool to further tackle the functional role of these cells in pathology. In a similar way, there are also no studies where mature and myelinating oligodendrocytes have been specifically depleted from the adult brain under pathological conditions. Probably these experiments are also very unlikely to be performed in the future, as oligodendrocytes were not shown to react to different kinds of injury besides providing new myelin during tissue repair, but remain rather stable.

Furthermore, the death of oligodendrocytes induces global demyelination as well as axonal defects already under healthy conditions Vanderluit et al. Summarizing this section, nothing has been published regarding ablation studies of oligodendrocyte lineage cells under pathological conditions. However, as especially for NG2-glia the already established methods have proven to be effective, very promising studies during pathological conditions will likely be investigated in the future.

This review summarizes the tremendous work of the last decades on the various ablation approaches in all types of glial cells in the adult brain see also Tables 1 — 4. Although these methods especially under healthy conditions seem quite similar at first sight, the nature of the cells requires different methodologies.

Using the DTA or DTR-system under a cell type specific promoter is a commonly shared and frequently used approach between all glial cell populations. This method has the advantage that it does not require specific features like the expression of a uniquely expressed surface receptor that can be targeted by a drug or being a uniquely mitotically active cell population, but can be applied to all cell types in a similar fashion when used with a specific promoter.

The side effects of this method also seem to be rather low and the efficiency quite high, wherefore this method is a very good candidate to be used for future ablation studies of any cell type. The use of cell specific pharmacological drugs is still an applicable and successful method to ablate cells, but has been so far only exploited for microglia Elmore et al. However, although these drugs are supposed to have a very high specificity for a cell type or a surface receptor, there might still be some receptor expression in other cell types, resulting in controversial outcomes of different studies like for instance in the case of the L-AAA-induced astrocyte ablation Saffran and Crutcher, ; Khurgel et al.

The same becomes true for microglia: although there are no controversial reports about the application of PLX to induce myeloid cell death, it is already known that the drug might cross-react with some other receptor-kinases like, e. For NG2-glia there are until now no cell specific drugs available, probably due to the lack of a unique promising target receptor on those cells.

In general, the use of cell specific pharmacological drugs still represents an easy and effective way for cell specific ablation studies that does in addition not require the use of expensive transgenic mouse lines. However, the risk of also targeting other cell populations and hence inducing potential secondary effects is still high and the experiments should — as always — be interpreted with caution. Another very commonly used but also very cell specific approach is the application of X-irradiation to a specific region of interest.

But this method can mainly be used for the ablation of NG2-glia, as they carry the unique feature of being the only proliferative cells outside the neurogenic niches, while microglia and astrocytes generally survive this treatment as they do not cycle under physiological conditions Xu et al. In this region, the proportion of slowly cycling NG2-glia was shown to be high in humans Geha et al.

However, it has also proven that X-irradiation is not very efficient to ablate NG2-glia, as this method mainly targets actively cycling cells, but NG2-glia were shown to be a very slowly cycling cell population and to have a very long cell cycle due to an extended G1-resting phase Simon et al.

This unique property is also the reason why infusion of the mitotic blocker AraC specifically ablates NG2-glia Robins et al. This variation could most likely first be explained by the use of different promoters like MBP or MOG that are driving the suicide gene expression. Even when using the same promoter, variations in the recombination rate and hence the ablation efficiency can occur, as the cloning strategy of the transgenic animals and the induction protocols can highly influence the recombination rate.

The application of the systemic prodrug that can either be given by injections or in the chow would increase the variability between the different studies, as one application form might be more efficient than another.

All these arguments do also apply when comparing the area specificity of the ablation approaches that also showed a high variability especially for astrocytes. After injury, the ablation approaches between at least microglia and astrocytes as so far no studies have been performed for cells of the oligodendrocyte lineage , are mainly using the TK as a mediator for apoptosis. Again, these studies proved to be quite efficient, both in terms of ablation efficiency and functional readout; might however be accompanied by some disadvantages.

TK-mediated cell ablation mainly targets proliferating cells, but not those that are quiescent Bush et al. Hence, the analysis of the function of another subpopulation of quiescent astrocytes would require another ablation method.

For microglia this bias does not seem to be so pronounced, as a higher proportion of microglia is able to proliferate after a pathological insult Amat et al.

Brain research generally has the tendency to look at different cell types in a very isolated way, as many of these ablation studies also did, both in the healthy and the pathological brain.

In those studies that also determined the consequences of the ablation in other cell types, only the cell numbers were quantified but not their function.

However, it is nowadays well accepted that a panglial network exists that is highly connected with each other via connexins May et al. It is, e. The ablation of one cell type in the brain could also elicit a reaction in other cell types even when only on the signaling level.

Unpublished data from our lab also indicate a cellular communication between the different glial cell types under pathological conditions: when genetically ablating NG2-glia after cortical stab wound injury, the cellular reactions of both astrocytes and microglia was hampered Schneider and Dimou, unpublished observations , similar to what has already been observed in the spinal cord after a diminished NG2-glia reactivity Rodriguez et al.

Taking these new findings into account, the overall sum of glial ablation studies can already provide insights in the cellular characteristics of these cells and help to better understand their function in both the healthy as well as the pathological brain.

However, looking to the future, they could be further exploited to investigate the almost unknown terrain of glial cell interactions in vivo. SJ structured and wrote the manuscript. LD gave structural and contextual input and corrected the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Akiyama, H. Brain microglia constitutively express beta-2 integrins. Amat, J. Phenotypic diversity and kinetics of proliferating microglia and astrocytes following cortical stab wounds. Glia 16, — Asai, H. Depletion of microglia and inhibition of exosome synthesis halt tau propagation.

Azevedo, F. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain.

Bardehle, S. Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation. Bergles, D. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature , — Glial cells and chronic pain. Kriegstein A, Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci. Evidence for a role of connexin 43 in trigeminal pain using RNA interference in vivo.

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These choices will be signaled globally to our partners and will not affect browsing data. We and our partners process data to: Actively scan device characteristics for identification. I Accept Show Purposes. Your central nervous system CNS is made up of your brain and the nerves of your spinal column.

Astrocytes The most common type of glial cell in the central nervous system is the astrocyte, which is also called astroglia. These include: Forming the blood-brain barrier BBB : The BBB is like a strict security system, only letting in substances that are supposed to be in your brain while keeping out things that could be harmful.

This filtering system is essential for keeping your brain healthy. Regulating neurotransmitters : Neurons communicate via chemical messengers called neurotransmitters. This reuptake process is the target of numerous medications, including anti-depressants. Cleaning up : Astrocytes also clean up what's left behind when a neuron dies, as well as excess potassium ions, which are chemicals that play an important role in nerve function.

An active region gets more than an inactive one. Synchronizing the activity of axons : Axons are long, thread-like parts of neurons and nerve cells that conduct electricity to send messages from one cell to another. Brain energy metabolism and homeostasis : Astrocytes regulate metabolism in the brain by storing glucose from the blood and provide this as fuel for neurons. This is one of their most important roles.

Astrocyte dysfunction has been potentially linked to numerous neurodegenerative diseases, including: Amyotrophic lateral sclerosis ALS or Lou Gehrig's disease Huntington's chorea Parkinson's disease. Oligodendrocytes Oligodendrocytes come from neural stem cells. Microglia As their name suggests, microglia are tiny glial cells. Along with Alzheimer's, illnesses that may be linked to microglial dysfunction include: Fibromyalgia Chronic neuropathic pain Autism spectrum disorders Schizophrenia Microglia are believed to have many jobs beyond that, including roles in learning-associated plasticity and guiding the development of the brain, in which they have an important housekeeping function.

Ependymal Cells Ependymal cells are primarily known for making up a membrane called the ependyma, which is a thin membrane lining the central canal of the spinal cord and the ventricles passageways of the brain. Radial Glia Radial glia are believed to be a type of stem cell , meaning that they create other cells. Schwann Cells Schwann cells are named for physiologist Theodor Schwann, who discovered them.

Diseases involving Schwann cells include: Guillain-Barre' syndrome Charcot-Marie-Tooth disease Schwannomatosis Chronic inflammatory demyelinating polyneuropathy Leprosy We've had some promising research on transplanting Schwann cells for spinal cord injury and other types of peripheral nerve damage.

Satellite Cells Satellite cells get their name from the way they surround certain neurons, with several satellites forming a sheath around the cellular surface. They're also believed to help transport several neurotransmitters and other substances, including: Glutamate GABA Norepinephrine Adenosine triphosphate Substance P Capsaicin Acetylcholine Satellite cells are linked to chronic pain involving peripheral tissue injury, nerve damage, and a systemic heightening of pain hyperalgesia that can result from chemotherapy.

A Word From Verywell Much of what we know, believe, or suspect about glial cells is new knowledge. Was this page helpful? Thanks for your feedback! Sign Up. What are your concerns? Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.

Related Articles. What Is an Axon? When any type of injury occurs, the Schwann cells are sent to the injury site to remove the dead cells. The Schwann cells also have the capability to occupy the original space of the neurons and regenerate the fibers in such a way that they are able to return to their original target sites. The precentral gyrus is the anatomical location of the primary motor cortex , which is what this gyrus is commonly known as.

The precentral gyrus is believed to contain the motor control for the torso, arms, hands, fingers, and head. Satellite cells small glia in the PNS that works by surrounding neurons in the sensory, sympathetic, and parasympathetic ganglia. Ganglia are clusters of nerve selves within the autonomic nervous system as well as the sensory system. The autonomic nervous system regulates the internal organs, whilst the sensory system is important for our senses to work. These cells are thought to be similar to astrocytes in the CNS as they work in similar ways.

These cells also absorb harmful toxins so that they do not damage the neurons, as well as detecting and responding to injury and disease in the same way that microglia do.

As previously discussed, glia cells are especially important for the overall functioning and support of neurons.

Therefore, if these cells are damaged in any way, can result in many complications, depending on the cells that have been damaged. Neurodegenerative disorders are particularly involved in glial damage. As microglia in particular is related to the immune system, other conditions which are linked to damaged microglia include chronic neuropathic pain and fibromyalgia. If microglia are prevented from responding to injury and disease, this can result in chronic pain for individuals.

Glial cells in general tend to degenerate in several neurodegenerative diseases, therefore loss of glial cells may contribute to the impairment of learning and memory. Abnormalities in the process of forming myelin sheath in the CNS through oligodendrocytes has been associated with behavioral and cognitive dysfunctions because of signaling of the neurons being weakened.

These dysfunctions have the potential to result in various mental health conditions such as schizophrenia and bipolar disorder. Dysfunction in forming myelin sheath in the PNS through Schwann cells can result in weakened reflexes, weakness, sensory loss, and sometimes paralysis.

This can result in symptoms such as numbness, weakness, and sometimes even death if it affects the muscles involved in respiration. Although this condition targets the axons of neurons, this also damages the Schwann cells as a result and makes them redundant. Guillain-Barre Syndrome can be treated through intravenous immunoglobulin which is a treatment comprised of blood donation that contain healthy antibodies, in order to prevent harmful antibodies damaging the axons of neurons.

Although there are not currently any known cures for neurodegenerative diseases that can affect glial cells, it has been suggested that some lifestyle changes can increase the number of new neurons and glial cells being produced. Exercising, eating healthy foods, and completing exercises for the mind have some support behind them for increasing the number of new cells in certain areas of the brain.

Olivia has been working as a support worker for adults with learning disabilities in Bristol for the last four years. Guy-Evans, O. Glial cells types and functions.