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History of Glia

Glia have a long history: they were first noted in 1824 and first named in 1856. While never as studied as neurons, the early neuroscientists studied and debated glia's classification, morphology, and roles. Very recently, more and more glial roles have been recognized and glia are being considered more active players in the nervous system than ever before. Many of the functions now recognized, however, were proposed by the earliest neuroscientists, such as glia's ability to secrete chemicals (Nageotte), their association with blood vessels (Golgi), their morphological plasticity (Cajal), their ability to electrically insulate (Cajal), their role in neurotransmitter uptake and termination (Lugaro), and role in pathology (Virchow).

Right: Abbreviated time line of important neuroscientists in glia's history. Click on images to enlarge.


The discovery of neuroglia is usually credited to Rudolf Virchow, a mid-nineteenth century German anatomist (Volterra Pref), but the first description of glia was much earlier, when French physician Rene Dutrochet noted small globules among the large globules of the mollusk nervous system in 1824 (Kettenman 3). Virchow, in 1856, was the first to name these structures, calling them "nevernkitt," meaning nerve-glue and translated to "neuroglia." He noticed that what he thought was connective tissue lining the ventricles of the brain actually extended into the tissue, and the name he granted the cells that made up this tissue suggests what he thought was its purpose – to fill in the spaces around neurons and hold them together (Somjen 1988). Otto Deiters also had a role in the earliest descriptions of non-neuronal nervous tissue, claiming the defining feature of these new cells was their lack of axons. Some of the cells he found meeting this description were in fact incompletely-stained neurons (see below) (Somjen 1988).

Left to right: two illustrations of glia from Deiters. The drawing on the left, from white matter, was probably an oligodendrocyte, but the middle drawing, from the hypoglossal nucleus, might have been a neuron whose axon was not visible (Somjen 1988, Fig. 2). The rightmost picture is Virchow's drawing of neuroglia. E, ependymal epithelium; v-w, blood vessel in "connective tissue"; N, nerve fibers; ca, copora amylacea--perhaps a staining artifact (Somjen 1988, Fig. 1).

Classification and Morphology:

Much of the early debates about glia came from disagreements about their classification, particularly around the question of their embryonic origins. Deiters was the first to suggest that these cells derived from the ectoderm, and were thus epithelial rather than connective tissue, as Virchow thought. Andriezen recognized two types of glia in 1893, ectodermal fibrous glia in the white matter of the central nervous system and mesoblastic protoplasmic glia in the gray matter. Ramon y Cajal agreed with the classification but argued that both came from the ectoderm. Note that these two types of glia are both what we recognize today as astrocytes; microglia and oligodendrocytes would not be recognized as glia until later. Ramon y Cajal also noted a non-glial third element without dendrites or polarity, which probably resulted from a staining artifact. In terms of form, there were several short-lived debates about the possibility that glial fibers detached from their originating cells, suggested by Weigert in 1895, and about the existence of a glial syncytial network, suggested by Held in 1903. In 1920, Pio del Rio-Hortega, a student of Cajal, classified the glia into four types: protoplasmic in gray matter, neuroglia in white matter, mesoblastic microglia, and interfascicular glia (what are now oligodendrocytes) (Somjen, 1988).

Left: Del Rio-Hortega's four types of glia. A: Gray matter protoplasmic neuroglia. B: White matter fibrous neuroglia. C: Microglia. D: White matter interfascicular glia (oligodendrocytes) (Somjen 1988, Fig. 4).

Glial Function:

Perhaps the most important early debate for the topic at hand is around the roles of glia. Virchow named glia after what he thought was their main role – structural support – but he also wrote that they were the most common site of pathology in the central nervous system (Hatton 6). Golgi argued that glia served a nutritive role for neurons. Because he believed dendrites in neurons also provided a nutritive function, the presence of similar processes in glia, but the absence of an axon, provided evidence for him that the entire cell had a nutritive role. Their close association with blood vessels provided further support to this theory. Santiago Ramon y Cajal, because he believed dendrites were involved in signaling and not just nutrients in neurons, disagreed with Golgi's hypothesis. Cajal also disagreed with Virchow's and Weigert's theory that glia simply filled the spaces in between neurons or left by dead neurons. Cajal believed instead that glia’s main role was to provide insulation to protect neurons from incorrect electrical signaling, a hypothesis developed originally by Santiago's brother Pedro Ramon y Cajal. Santiago Ramon y Cajal thought at the time that myelin was not glial, so he could not explain why white matter would have both myelin and glia, since the myelin was clearly better axonal insulation. Although Penfield did recgonize that myelin was glial in 1924, Cajal's dilemma of both myelin and glia in white matter did suggest the existence of another role for astrocytes (Somjen 1988). Cajal also proposed that glia could have a role in sleep by extending "their processes into synapses, reducing their activity...when astrocytic processes retract, neurons would contact one another and thus become active again" (Hatton 6).

There were other scientists that believed glia had much more active roles. Marinesco recognized in 1896 glia’s role in the phagocytosis of neurons. Nageotte suggested in 1910 that glia were part of the endocrine system and could secrete substances into the blood stream. Achucarro furthered this idea and suggested that these secretions into the blood linked the central and peripheral nervous systems in 1915. Lugaro, in 1907, suggested many roles glial cells, including guiding neuronal migration in development and maintaining and detoxifying the interstitial fluid. He even predicted a glial role in the synapse, suggesting that glia could terminate synaptic action by chemically altering or taking up neurotransmitters (Somjen 1988).

Right: Ramon y Cajal's illustration of protoplasmic astrocytes. A: astrocyte. B: neuron. a and b: pericellularpedicls. c: fine perivascular pedicle. (Somjen 1988, Fig. 3)


Structural and Chemical Description
With the invention of the electron microscopy, investigations into the ultrastructure of astrocytes were undertaken by several scientists, including Luse in 1956, Farquhar and Hartmann in 1957, Bunge in 1960, De Roberts and Gershenfeld in 1961, and Palay in 1962. In terms of chemical markers, Eng et al. and Bignami et al. indetified the glial fibrillary acidic protein, GFAP (1971 and 1972, respectively). This protein was found to be associated with astrocyte intermediate filaments, and though it is found not in all astrocytes, it has been particularly important in identifying astrocytes. Additionally, Moore identified the S-100 protein, Sommer et al. identified the C1 antigen in Bergmann glia and retinal Muller cells, and Lagenaur et al. found the M1 antigen in proplasmic and fibrous astrocytes, all of which help identify glia in immuncocytochemistry today (Kettenman 4).

Glial Interactions with Neurons
The first evidence that glia respond to neuronal signaling came from Hyden in 1960's. He found that, based on protein content, RNA content, and other biochemcial indicators, glia underwent biochemical changes in certain parts of the brain associated with a training procedures. Many flaws have been found with his methods, but the work foreshadowed the emerging idea of the tripartite synapse. More concrete evidence for glial-neuronal communication came from Kuffler's elctrophysiological studies. They found a negative glial membrane potential, permeability to potassium, glial gap junctions, and glial slow depolarizing currents. These slow depolarizing currents occurred in response to neuronal activity and correlated with accumulations of potassium in the extracellular space. Kuffler and Nicholls, in 1965, speculated that the accumulation of potassium was a form of cellular signaling. This hypothesis was confirmed when it was found by Rose and Ransom in 1996 that the potassium in the ECS causes glia to take up potassium, by Ransom alone in 2000 that this "signal" also causes glia to export protons, and by Hof et al. and Brown et al. in 1988 and 2000, respectively, that the potassium in the ECS induces glia to break down glycogen (Hatton 7-8).


Author(s) Year Title Publication Info Link
G. Somjen 1988 Nervenkitt: Notes on the History of the Concept of Neuroglia Glia PDF
G. Hatton and V. Parpura 2004 Glial-Neuronal Signaling Boston: Kluwer Academic Publishers Josiah
A. Volterra, P. Magistretti, and P. Haydon 2002 The Tripartite Synapse Oxford: Oxford University Press Josiah
H. Kettenmann and B Ransom 1995 Neuroglia New York: Oxford University Press Josiah

Recommended Reading

Author(s) Year Title Publication Info Link
S. Ramon y Cajal 1995 Histology of the Nervous System of Man and Vertebrates, ch. 8 New York: Oxford University Press Josiah
S. Ramon y Cajal 1984 The Neuron and the Glial Cell, ch. 8 Springfield: C.C. Thomas Josiah
Last edited by hleblanc on Dec 07, 2010 07:07
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