Does Glial Cells Have Any Role in Generating & Propagating Creative Thought ? Nearly 80 – 90 % of the Brain is Composed of Glia.

Until recently, neuroscientists thought glial cells did little more than hold your brain together. But in the past few years, they’ve discovered that glial cells are extraordinarily important. In fact, they may hold the key to understanding intelligence, treating psychiatric disorders and brain injuries and perhaps even curing fatal conditions like Alzheimer’s, Parkinson’s, and Lou Gehrig’s Disease.

In The Root of Thought, leading neuroscientist Dr. Andrew Koob reveals what we’ve learned about these remarkable cells, from their unexpected role in information storage to their function as adult stem cells that can keep your brain growing and adapting longer than scientists ever imagined possible.

Ranging from fruit flies to Einstein, Koob reveals the surprising correlation between intelligence and the brain’s percentage of glial cells – and why these cells’ unique wavelike communications may be especially conducive to the fluid information processing human beings depend upon.

Here’s an introductory teaser to five types of glia researchers have discovered so far:

Astrocytes: The star-shaped astrocyte uses thousands of arms to take up neurotransmitters, cleaning up after neuronal activity. Scientists suspect that they’re the most common type of glial cell in the brain, and some believe that the calcium waves astrocytes generate may underlie creative thought.

Oligodendrocytes: The octopus-like oligodendrocyte wraps the tips of its tentacles around axons in a fatty white coating called myelin. Studying such ‘white matter’ may provide insights into intelligence and learning and problems with myelin are at the heart of diseases such as multiple sclerosis.

Schwann cells: Much like an oligodendrocyte’s protective tentacles, Schwann cells form a snug layer of myelin around the axon like the bread around a corn dog. As the only glial cell in the peripheral nervous system—the nerves outside the brain and spinal cord—Schwann cells adopt a range of different roles, including astrocyte-like chemical clean ups.

Microglia: While the previous three cells belong to a category called macroglia, there are also smaller microglia. These wee cells are the brain’s rapid response team. Since the immune system’s molecular machines can’t cross the blood-brain barrier, the versatile microglia defends the brain from invaders.

NG2 Cells: Their name may not be that memorable, but NG2s—or the cell previously known as “oligodendrocyte precursor cells“—are big news in the world of glia research and may even constitute a whole new category of macroglia. These cells transform not only into different kinds of glia, such as oligodendrocytes and astrocytes but also into neurones, further blurring the lines that distinguish the two types of cells.


Astrocytes are shown in red, OPCs in green, and neurones in blue. The cells are taken from rat hippocampus and grown in culture. Credit:  Dr. Jonathan Cohen, NICHD. R. Douglas Fields, Ph. D. is the Chief of the Nervous System Development and Plasticity Section at the National Institute of Child Health and Human Development and Adjunct Professor at the University of Maryland, College Park. Fields, who conducted postdoctoral research at Stanford University, Yale University, and the NIH, is Editor-in-Chief of the journal Neuron Glia Biology and a member of the editorial board of several other journals in the field of neuroscience.

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Káradóttir et al report that some NG2+ glia can be induced to fire action potentials by excitatory synaptic input (highlighted by red starbursts) formed by myelinated (top) or unmyelinated (bottom) axons. The physiological role of NG2+ cell excitability is not yet clear, but, as suggested by the authors, may influence the transition of NG2+ cells into myelinating oligodendrocytes. These NG2+ cells have processes that wrap nodes of Ranvier, and they might, therefore, be well positioned for a role in optimising nodal spacing or stability. Image source

One learns how crucial glial cells grow and develop

why almost all brain tumours are comprised of glial cells and

the potential implications for treatment

even the apparent role of glial cells in our every thought and dream!



The structures within the brain are made up of about 100 billion neurons, as well as trillions of support cells called glia. Neurons may be the more important cells in the brain that relay messages about what you’re thinking, feeling, or doing. But they couldn’t do it without a little help from their friends, the glial cells.  There are a few different types of glia in the brain: oligodendrocytes, microglia, and astrocytes. Each is needed to optimize brain function. Oligodendrocytes are specialized cells that wrap tightly around axons to form the myelin sheath. These cells speed up the electrical signals (action potentials) that travel down an axon. Without oligodendrocytes, an action potential would travel down an axon 30 times slower!



Microglia are mesodermal in origin.



Astrocytes are star-shaped glia that hold neurons in place, supply nutrients, and digest parts of dead neurons. But because astrocytes cannot generate action potentials, they haven’t gotten much attention, until recently. Astrocytes can actually communicate with neurons and modify the signals they send and receive. That means astrocytes are much more involved than we once thought in both the processing of information, and the signaling at the synapse.



Astrocytes appear to be involved in almost all aspects of brain function. Scientists want to know more about how gliotransmitters can inhibit, stimulate, or fine-tune the action potentials fired by neurons. But astrocytes may even do more. There is growing evidence that astrocytes can alter how a neuron is built by directing where to make synapses or dendritic spines. They can also attract new cells (like immune cells and perhaps even adult neural stem cells) to repair damage. The Future of Gliotransmission Knowing more about astrocytes will also shed light on diseases in which communication between astrocytes and neurons is altered, including Alzheimer’s disease, AIDS, brain cancer, and ALS (amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease).


Why glia have been overlooked for centuries, and how new experiments with glial cells shed light on some of the most mysterious aspects of the mind?

Originally, scientists didn’t think they did anything.  Until the last 20 years, brain scientists believed neurones communicated to each other, represented our thoughts, and that glia were kind of like stucco (A plaster now made mostly from Portland cement and sand and lime; applied while soft to cover exterior walls or surfaces) and mortar holding the house together.  They were considered simple insulators for neurone communication.

There are a few types of glial cells, but recently scientists have begun to focus on a particular type of glial cell called the ‘astrocyte’, as they are abundant in the cortex.

Interestingly, as you go up the evolutionary ladder, astrocytes in the cortex increase in size and number, with humans having the most astrocytes and also the biggest

Scientists have also discovered that astrocytes communicate to themselves in the cortex and are also capable of sending information to neurones.

Finally, ‘astrocytes’ are also the

adult stem cell in the brain [Subventricular Zone Astrocytes Are Neural Stem Cells in the Adult Mammalian Brain.]

  • There is another study which identifies Ependymal cells as neural stem cells.[Identification of a Neural Stem Cell in the Adult Mammalian Central Nervous System]. New neurons are continuously generated in specific regions of the adult mammalian brain. These neurons are derived from multipotent stem cells, the identity of which has been enigmatic. We show here that ependymal cells are neural stem cells and that they generate olfactory bulb neurons. Ependymal cells divide rarely, but after an injury the proliferation rate increases and their progeny migrates to the site of the lesion, where they differentiate to astrocytes.

and astrocytes control blood flow to regions of brain activity. Because of all these important properties, and since the cortex is believed responsible for higher thought, scientists have started to realize that astrocytes must contribute to thought.

Why have glia been neglected for so long?

To understand this, you have to take a tour of the history of brain science.

Glia were mainly a sidebar for 200 years in the struggle over the idea of the neurone.

A few highlights were: In the late 18th century, scientists discovered the electrical properties of the neurone in the spine of frogs. Neurones have long tethers that are easy to study called ‘axons’ that extend from the cell body from the brain into the spine and the spine out to the limbs and body. Similarly, neurones in the senses were linked to the neurones in the brain. This is where the notion of neurones as the base of our thoughts took root. In the mid-19th century, glia were just being discovered, and researchers figured the glial cells simply held the neurones together (glia is greek for glue).

What I find sort of hilarious is that scientists stumbled upon a very numerous cell in the brain, an organ responsible for our thoughts and personality, but they were so focused on neurones that they concluded the new cell was worthless. In the late 19th century a staining method was developed to look at cells more effectively in the brain.

A brilliant researcher from Spain, Santiago Ramon y Cajal, took it upon himself to study the brain from the perspective of neurons. He meticulously mapped out a scheme for how they process information and are connected, which led to “The Neuron Doctrine.”  (“The Neuron Doctrine” is a belief that neurons are responsible for our thoughts.)

However, Cajal seemed inconvenienced by glial cells. They were very numerous and obviously hanging out all over the cortex.  Meanwhile, his brother Pedro, who was also a scientist, developed the theory that glial cells were ‘support cells’ that insulated neuron electrical propertiesCajal decided to back his brother’s theory.  And since 1906 when he won the Nobel prize, this has been the dogma. (A doctrine or code of beliefs accepted as authoritative)

Some of the early experiments that first led scientists to reconsider the role of glial cells?

Glial experiments didn’t get going until the 1960s. All scientists knew about glia was that if you put neurones in a petri dish, you had to have glia, or neurones would die. Then, Stephen W. Kuffler at Harvard, for reasons unknown, decided to test Pedro’s accepted theory of insulation. This was around same time that cell counts in the brain revealed glial cells to be nearly 90% of the brain (this is where the neurone based idea that we only use 10% of our brain comes from). Kuffler is notable because he ironically established the Harvard ‘neuro’ biology department while he was performing these groundbreaking glial experiments.

Anyway, Kuffler took astrocytes from the leech and mud puppy and added potassium, something that is known to flow out of neurons after they are stimulated. He thought this would confirm Pedro’s theory that glial cells were insulators. What he found instead was that the electrical potential of glial cells responded to potassium. Kuffler and colleagues found that astrocytes exhibited an electrical potential, much like neurons. They also discovered in the frog and the leech that astrocytes were influenced by neuronal ion exchange, a process long held to be the chemical counterpart to thought. Since then many researchers have completed experiments on the communicatory ability of glial cells with neurons, including in the late 80s and early 90s when it was discovered glial cells respond to and release ‘neuro’ transmitters.

Why are calcium waves important?

In short, calcium waves are how astrocytes communicate to themselves. Astrocytes have hundreds of ‘endfeet’ spreading out from their body. They look like mini octopi, and they link these endfeet with blood vessels, other astrocytes and neuronal synapses. Calcium is released from internal stores in astrocytes as they are stimulated, then calcium travels through their endfeet to other astrocytes. The term ‘calcium waves’ describes the calcium release and exchange between astrocytes, and between, astrocytes and neurons. Scientists at Yale, most notably Ann H. Cornell-Bell and Steven Finkbeiner, have shown that calcium waves can spread from the point of stimulation of one astrocyte to all other astrocytes in an area hundreds of times the size of the original astrocyte.

Furthermore, calcium waves can also cause neurones to fire.

And calcium waves in the cortex are leading scientists to infer that this style of communication may be conducive to the processing of certain thoughts.

If that isn’t convincing, it was recently shown that a molecule that stimulates the same receptors as Tetrahydrocannabinol (THC) can ignite astrocyte calcium release.

Glia and their calcium waves might play a role in creativity.

This idea stems from dreams, sensory deprivation and day dreaming.

Without input from our senses through neurones, how is it that we have such vivid thoughts?

How is it that when we are deep in thought we seemingly shut off everything in the environment around us?

In this theory, neurones are tied to our muscular action and external senses. We know astrocytes monitor neurones for this information. Similarly, they can induce neurones to fire. Therefore, astrocytes modulate neurone behaviour.

This could mean that calcium waves in astrocytes are our thinking mind.

Neuronal activity without astrocyte processing is a simple reflex; anything more complicated might require astrocyte processing.

The fact that humans have the most abundant and largest astrocytes of any animal and we are capable of creativity and imagination also lends credence to this speculation.

Calcium is also released randomly and without stimulation from astrocytes’ internal stores in small bursts called ‘puffs.’ These random puffs can lead to waves. It is possible that the seemingly random thoughts during dreams and sensory deprivation experience could be calcium puffs becoming waves in our astrocytes.

Basically, it is obvious that astrocytes are involved in brain processing in the cortex, but the main questions are,

Do our thoughts and imagination stem from astrocytes working together with neurones, or are our thoughts and imagination solely the domain of astrocytes?

Maybe the role of neurones is to support astrocytes.


Adapted from

Andrew Koob

The Root of Thought: What Do Glial Cells Do? 

Andrew Koob received his PhD in neuroscience from Purdue University in 2005 and has held research positions at Dartmouth College, the University of California, San Diego, and the University of Munich, Germany. He’s also the author of The Root of Thought, which explores the purpose and function of glial cells, the most abundant cell type in the brain

A Brief Historical Perspective


 The Concept of Neuroglia: A Historical Perspective

Image Credit

Virchow’s illustration of neuroglia.

A. Ependyma and neuroglia in the floor of the fourth ventricle. Between the ependyma and the nerve fibres is “the free portion of the neuroglia with numerous connective tissue corpuscles and nuclei.” Numerous corpora amylacea are also visible, shown enlarged below the main illustration (ca).

E: ependymal epithelium;

N: nerve fibres;

v-w: blood vessel.

B: Elements of neuroglia from white matter of the human cerebral hemispheres.

a. free nuclei with nucleoli;

b. nuclei with partially destroyed cell bodies;

c: complete cells. (From Virchow, 1858.)

We may conclude, therefore (although it is not emphasised in most historical accounts), that Virchow in 1856 used the term neuroglia to refer to the interstitial substance, not to the cellular elements within it. Time has blurred this distinction.

What then is Virchow’s interstitial substance or tissue in today’s terms?

It is undoubtedly the complex, space-filling processes of macroglial cells, especially astrocytes (Nedergaard et al., 2003). So, in retrospect, the meaning of Virchow’s term neuroglia morphed to accommodate the reality that neuroglial cells are the material between neurones. In other words, the two terms, neuroglia and neuroglial cells, soon became synonymous.


 The Concept of Neuroglia: A Historical Perspective

Image Credit

Retinal neuroglial cells.

A. Cross section of frog retina. Note the radial (i.e., Müller) cells with their characteristic endfeet in the layer numbered “8.”

B. Isolated radial fibres from the frog retina.

C. Müller fibres of the sheep retina. Brush-like processes extend from the Müller fibre in the outer granular layer (labelled y); b. very delicate network of fenestrated membranes similar to those in the ganglion cell layer; c. network in the molecular layer; d. nuclei shown as part of the Müller fibres; e. cavity in which the nuclei or the cells of the internal granular layer are located.

A and B from Müller (1856). C from Schultze (1859).


 The Concept of Neuroglia: A Historical Perspective

Image Credit

Deiters’ illustrations of connective tissue cells.

A. Connective tissue cell from white matter.

B. Connective tissue cell from grey matter (hypoglossal nucleus). (From Deiters, 1865.)

C. The section from the spinal cord of the ox stained by carmine after chromic acid preparation. 1. grey matter; 2. white matter with exposed axons; multipolar connective tissue cells (magnification 400×). (From Henle and Merkel, 1869.)


 The Concept of Neuroglia: A Historical Perspective

Image Credit

Neuroglial cells depicted in Golgi’s early work.

A. a. Neuroglial cell from the superficial layer of the cerebral cortex; b. neuroglial cell from the deeper cortical layer of the

cerebrum from a 2-month-old child. The cell bodies and proximal processes contain fat droplets.

B. Slice of the cerebral cortex hardened in osmium; a. blood vessel; b. neuroglial cells with multiple thread-like processes;

c. processes from neuroglial cells terminating on the vessel wall.

C. Section through deep white matter tracts. Between the axons and directly attached are several flattened neuroglial cells.

Neuroglial processes project in all directions among the axons and attach to their ensheathments.

D. Neuroglial cells in white matter. Longitudinal view of neuroglial cells showing their relationship to axons. All panels from Golgi (1894).

Golgi’s greatest contribution, some would argue, was his famous ‘La reaziona nera’, or ‘the black reaction’, that permitted entire neurones and glial cells to be stained. While this method (potassium dichromate-silver) did not distinguish between neurones and neuroglia, it allowed them to be visualised better than ever before and in their entirety. Only later would specific stains for neuroglia appear (Cajal, 1913; Rio-Hortega, 1919).

So impressive were the gains in knowledge that by 1909 Cajal could say (Cajal, 1995): “We have emphasised that two special elements, which are really abstractions derived from many examples, form all neural tissue: the neurone with its various processes and the glial cell.”

Image Credit

Vertical slice from the human cerebellum showing the glial cells in this structure, including the Golgi epithelial cells (also known as Bergmann glial cells). (From Golgi (1894).


In 1893 Michael von Lenhossek (1863–1937) from Würzburg introduced the term astrocyte to refer to star-shaped neuroglial cells. Because Virchow thought that neuroglia constituted connective tissue, it was assumed that these cells must arise from mesoderm. This idea died slowly. The failure of connective tissue stains, increasingly specific for mesoderm, to stain these cells was one line of evidence refuting the idea that they were mesodermal, but it left open the defence that negative results might only mean that neuroglial cells were a special type of connective tissue. Wilhelm His (1831–1904) studied early development and recognized that neuroblasts and spongioblasts, which formed radial glia, are both of ectodermal origin (His, 1889). Lenhossek (1893) showed that the radially aligned spongioblasts transformed into astrocytes (Fig. 1.6 B) (later confirmed by Cajal [1913]). These findings were finally accepted as definitive proof that astrocytes were of ectodermal origin.

Another long-standing misimpression was that neuroglial cells formed a physical syncytium, often called the neurospongium (His, 1889). In retrospect, this mistake was mainly a consequence of limited microscopic resolution and misleading staining techniques. It was seriously questioned by many, including Lenhossek and Cajal, whose studies using the Golgi technique showed separate glial cells that transitioned from radial glial cells to typical astrocytes during development. The syncytium theory also came under attack when it became apparent that a normal glial cell could exist immediately adjacent to a glial cell showing marked pathological change; this did not make sense if the cells were continuous with one another. Unassailable evidence, however, was not provided until the 1950s, when the newly developed electron microscope showed that glial cells are always separated from each other by a thin layer of extracellular space.

Image Credit

Astrocytes and radial glia in material prepared by Lenhossek in 1893.

A: Supportive cells (i.e. astrocytes) from the spinal cord of a 9-month-old child; Golgi impregnation.

B. The spinal cord of a 14 cm human embryo; Golgi impregnation of the supportive cells. Left: ependymal (i.e., radial glial) scaffold. Right: precursors of spider cells (astroblasts). (From Lenhossek, 1893.)


The term Schwann cell appears to have been first used by Louis-Antoine Ranvier (1835–1922) in 1871, but it may not have come into common usage until Cajal’s treatise was published in 1909.

Virchow enters the picture again in the story about peripheral glia. He introduced the term myelin in 1858 to refer to the fatty sheath surrounding some axons: “It is this substance, for which I have proposed the name of medullary matter (Markstoff), or myeline, that in extremely large quantity fills up the interval between the axis-cylinder and the sheath in primitive nerve fibers” (Virchow, 1978). He, like many of his contemporaries, felt that myelin was secreted by the axon, not made by the Schwann cell. For example, in 1909 Cajal states: “Also, many writers, including ourselves, view myelin itself as nothing more than a secretory product of axons, rather than the contents of a cell that the axon passes through.” This concept endured as long as it did, in part, because central nervous system (CNS) myelin appeared not to be associated with nuclei; in the apparent absence of a cell to make myelin, it seemed logical that the axon must make it. Ranvier was not the first to see interruptions in the myelin covering axons, but he was the first to realize that these interruptions were not artifacts. He correctly perceived that the axon was passing through a series of independent myelin segments and that each segment was associated with a single Schwann cell (Ranvier, 1872).


In Histology of the Nervous System, Cajal (1995) summarised what was known about the functions of glia. He did not consider Schwann cells glia and, microglia and oligodendrocytes were not yet discovered, so his discussion was exclusively about astrocytes. He begins with these prescient (perceiving the significance of events before they occur) remarks: “What is the function of glial cells in neural centres? The answer is still not known, and the problem is even more serious because it may remain unsolved for many years to come until physiologists find direct methods to attack it.”

He first addressed the suggestion by Golgi and his students that glial cells carry important nutritional fluids from capillaries to neuronal cell bodies.This idea was spawned by Golgi’s observation that most astrocytes contact capillaries with their processes.

Cajal raised objections to this hypothesis:

(1) Glial cells that surround neurones often lack processes that contact capillaries. He may have been referring, without realising it, to perineuronal oligodendrocytes. However, he illustrates protoplasmic astrocytes from adult human grey matter with processes “never appearing to end near capillaries.” In retrospect, limitations imposed by available staining methods and microscopes probably caused him to overestimate this population.

(2) Amphibian and fish white matter does not contain glia. Subsequent studies have at least partially refuted this statement. Nevertheless, Cajal’s disregard for this theory was echoed nearly 60 years later in Kuffler and Nicholl’s review (1966). Only in the past 15 years has the nutritional theory of Golgi experienced an evidence-based renaissance.

Cajal carefully considered the filling theory of Weigert: “According to the celebrated neurologist, Weigert, glia serves an entirely passive role, filling spaces not occupied by neurones.” Cajal strongly denigrated (cause to seem less serious; play down) this notion based on careful reasoning. Despite his disdain, however, similar ideas have persisted and are sometimes encountered even today (Ransom et al., 2003).

The isolation theory developed by his brother, P. Ramon y Cajal, received strong support. The premise was that astrocytes act as physical insulation against the passage of neuronal impulses. “These processes are always arranged so as to prevent contact between either unmyelinated axons or dendrites, or between axons and dendrites, but only at points where these two different kinds of neuronal process should not lie immediately adjacent to one another” (Cajal, 1995). In white matter, he and others of this period intuitively assigned insulating function to myelin, which posed a nasty riddle: Why are there astrocytes in white matter? Cajal had no answer.

Ironically, he failed to appreciate the glial origin of myelin and so was denied the key insight that makes the isolation theory credible today, at least in regard to the oligodendrocyte.


Cajal’s understudy, Pio del Rio-Hortega (1882–1945), took up the problem of glial cells and developed his own stain (silver carbonate) that selectively stained the third element cells (Rio-Hortega, 1921). Two distinct cell populations emerged, which he named oligodendroglia (and later called oligodendrocytes to make the nomenclature consistent for the two forms of macroglia) and microglia. Oligodendrocytes, so named because they exhibited fewer and smaller branches than astrocytes, were felt to be true classical neuroglial cells of ectodermal origin (Rio-Hortega, 1928).

Image Credit

Early photomicrographs of oligodendrocytes and microglia.

Left panel: interfascicular oligodendrocytes form a sheath about the myelin segments. Right panels, A–I. Evolution of microglial cells during phagocytic activity.

A. Cell with thick, rough processes;

B. cells with short processes and an enlarged cell body;

C. hypertrophic cell with pseudopodia;

E. ameboid form;

F. cell with phagocytosed leukocyte;

G. cell with numerous phagocytosed red cells;

H. fat granule cell:

I. cell in mitotic divisions. Left panel from Rio-Hortega (1928). A-I from Rio-Hortega (1932).

Rio-Hortega recognised that oligodendrocytes were most common in white matter. He considered the oligodendroglia to be a member of the macroglial or classical neuroglial family. Because these cells had a relationship to myelin sheaths that bore a striking resemblance to the relationship between Schwann cells and the myelin sheaths of peripheral fibres, he proposed that oligodendrocytes made and sustained CNS myelin.

Microglia were viewed by Rio-Hortega as distinct from all other neuroglial cells because his studies showed them to be of mesodermal origin and to have migratory and phagocytic capabilities. Rio-Hortega summed up his position on the microglial cell as follows: “Since it is of different ancestry and its characteristics differ from those of the nerve cells (first element) and the neuroglial astrocytes (second element*), the microglia constitutes the true third element of the central nervous system” (Rio-Hortega, 1932). He acknowledged that microglia were the same cells, or closely related cells, as seen earlier by pathologists such as Nissl (1899; i.e., rod cells). In fact, Nissl and Alzheimer had argued that the glial cells seen under pathological conditions were of mesodermal origin.

Rio-Hortega’s accomplishments in rigorously defining the final two members of the CNS glial family and in deducing their functions are impressive. He was the first to describe the two types of microglia: ameboid and ramified. He recognised that the ameboid form was mobile and phagocytic ??? and was similar to a blood macrophage. In fact, he believed, as is believed today, that microglial cells originate from peripheral macrophages. He understood that the microglial cell can transform from its relatively inactive ramified form into the phagocytic ameboid form in response to a threat like the infection. “In historical perspective, we see that what Cajal is to the neurone, Rio-Hortega is to the neuroglia” (Jacobsen, 1993).

Image Credit

Illustration of cells stained with the platinum method of Robertson.

Composite diagram showing (1) “large pyramidal nerve cell of the cerebral cortex of sheep” and (2) “Three branching cells in the cerebral cortex of dog.” The cells labelled 2 were either microglia or oligodendrocytes. (From Robertson, (1899.)


Image Credit

Neuroglial cells in pathological situations.

A, B. Different types of glial cells found in multiple sclerosis plaques of the human cortex.   C. Glial cell close to a 14-day-old haemorrhage in the human white matter. Axons pass through the network of the cell. D. Rod cells stained with toluidine blue. E. Gitter cells stained with toluidine blue. A and B from Frommann (1878). C from Alzheimer (1910). D and E from Alzheimer (1904).

Image Credit

Relationship between (Alzheimer) plaque and glial cells; gaz: neuron; glz: glial cell; P 1: central part of the plaque; P 2: peripheral part of the plaque. (From Alzheimer, 1911.)

In studying brains from deceased multiple sclerosis patients, Carl Frommann (1831–1892) noted that glial cells underwent changes in the demyelinated plaques (Frommann, 1864). He believed that the cells in the areas of fiber degeneration were glial cells that had undergone morphological changes. He stated that the cells became larger and had fewer processes compared to normal glia. It was also clear to him that glial cells were still present in the degenerated areas despite the fiber loss (Fig. 1.10 A,B). He also claimed that some of the glial cells lacked a nucleus. In retrospect, it is likely that he observed activated microglia in these areas of fiber degeneration.

Franz Nissl (1860–1919) noted two new cell types that appeared in the pathological brain. One form was elongated and bipolar in shape, and he called such cells Stäbchenzellen (rod cells). He described this cell type in brains of demented patients but found them also in animals. He originally described these cells as glial elements (Nissl, 1899) but later considered the possibility that they were of mesodermal origin (Nissl, 1904). A second cell type was found mainly in pathological tissue associated with disruption of the blood–brain barrier. These cells were round, without processes, and he termed them Körnerzellen (granule cells) or Gitterzellen (lattice cells). Nissl speculated that they were infiltrating blood cells.

In 1910, Alois Alzheimer (1864–1915) published a book chapter summarizing the responses of neuroglia to different pathologies. It was clear to him and his contemporaries that any type of pathology is accompanied by a glial response. He described ameboid glial cells, or ameboid change, in response to both acute and chronic diseases of the nervous system. The ameboid glial cell was believed to be a transformed astrocyte (swollen, with granular cytoplasm and fragmented processes). Unfortunately, these cells were often, and easily, confused with Gitterzellen, as alluded to above. Alzheimer’s discussion about these cells is a good example of how static microscopic images were used to draw conclusions about function. “The ameboid glial cells do not share the task of glia to provide structural support. They do not form fibers and networks, but they appear at areas of neuronal degeneration. They develop probably in response to a stimulus from the degradation products. Since we did not observe that they take up neuronal structures, we have to assume that they help to liquefy them. This we conclude from our observations on ganglion cells. Over time they grow in size and replace the ganglion cells which will completely disappear and they can be found everywhere in the (degenerating) tissue. This leads to the conclusion that they assimilate the products generated by the degradation of the ganglion cell and neuronal structures. After reaching the peak of their development, they undergo regressive changes while producing various granula and deteriorate rapidly. Their degradation products move to the lymphatic and perivascular space as fluid phase and are there taken up by mesodermal cells to be converted to lipoid matter. Thus, they clean the nervous tissue from waste, transform it to a substance harmless to ectodermal tissue and deliver it to the mesodermal tissue” (Alzheimer, 1910).

In addition to relating the occurrence of ameboid glia to neuronal degeneration, as in the case of acute postmortem change, Alzheimer realised that they could be present in chronic diseases such as epilepsy and syphilis. He also confirmed their presence in the disease that bears his name. His histopathological analysis of the first dementia patient illustrated activated glial cells surrounding the plaques. His insights promoted glial cells to the status of important cellular elements in brain pathology. It was, however, Rio-Hortega who defined these pathological cell types and distinguished between astrocytes and microglia.


The early historical path to understanding neuroglia was circuitous (marked by obliqueness or indirection in speech or conduct) . Penfield’s general comment about the journey is telling: “Knowledge of the form and function of neuroglia is the result of progressive improvement in histological technique in the hands of careful workers. … Insight into the principles involved has been made difficult by numerous uncritical publications of men who, although doubtless sincere, are opportunists rather than cytologists” (Penfield, 1932). The essence of his sentiments continues to be valid today. The history of discoveries about neuroglia highlights a major obstacle to rapid scientific progress. Scientists become so attached to their theories that contradictory evidence fails to modify their viewpoint. When conflicting data appear, new arguments are concocted to preserve the attacked notion. When evidence emerged that myelin was formed by cells, and not by axons, these contrary findings failed to convince the faithful committed to the older idea. It is provocative to ask ourselves what evidence would be necessary for us to abandon our own pet theories. Historians of our own era will, undoubtedly, have many examples to choose from to illustrate this point.

Rio-Hortega considered the oligodendroglia to be a member of the macroglial or classical neuroglial family.