Nervenkitt: Notes on the history of the concept of neuroglia

GLIA 1:2-9 (1988)
Nervenkitt: Notes on the History of the
Concept of Neuroglia
GEORGE G. SOMJEN
Department of Physiology, Duke University Medical Center, Durham, North Carolina 27710
KEY
WORDS
Discovery of astrocytes, Discovery of microglia, Discovery of
oligodendrocytes
ABSTRACT
The evolution of concepts concerning the identity and the functions of
neuroglia is traced. Some of the main ideas in the works of Virchow, Deiters, Golgi,
Lenhossek, Lugaro, Ram6n y Cajal, del Rio-Hortega, Achucarro, Penfield, and others are
highlighted.
INTRODUCTION
It is striking to realize how much of today’s neurobiology research is directed toward answering questions
that were first asked about a century ago. Much of what
seemed mysterious then has become clear, not because
our generation is smarter than the ones before us, but
because we have the gadgets they missed. There is,
however, one area in which we seem to be almost as
confused as they were: it is that of the functions of glial
cells.
This article is not meant to cover the history of research relating to glia; that would require more time
and more pages than are available. Rather, i t is intended to highlight the historically significant ideas concerning the identity and nature of glia, especially those
that seem relevant, interesting, or entertaining for readers today. If accused of arbitrary selection, I shall readily
plead guilty. In the search for material I was greatly
helped by the bibliographies compiled by Penfeld (1932),
Glees (19551, and Windle (1958). A good summary of
what was known a t the turn of the century has been
written (in English!) by Robertson (1897).
It is customary to credit Virchow with the discovery of
glia. Strictly speaking, this is not correct. What Virchow
described does not exactly correspond to what we today
consider to be glial tissue. He did, so to speak, start the
ball rolling by opposing the opinion held by many of the
most prestigious authorities before him, including for
example Purkinje. Virchow felt compelled to argue
against the notion that the brain contains no connective
tissue, and that the ependyma ventriculorum is but a
single layer of epithelium. As a practicing pathologist,
he was familiar with inflammatory processes that can
afflict the ventricular cavities of the brain. To Virchow
it seemed evident that only connective tissue is capable
0 1988 Alan R. Liss, Inc.
of becoming inflamed, and therefore he was convinced
that underneath the single-cell layer of ependyma the
ventricles must be lined by a sheet of connective tissue.
With this idea in mind he went to work and found, or
thought he found, a connective tissue not only beneath
the ependyma, but penetrating into the mass of the
brain, filling all interstices among nerve cells and their
fibers, and also separating nervous tissue from blood
vessels. In the collection of Virchow’s papers published
in 1856 there is a footnote to a n article that first appeared in 1846, in which he wrote: “this connective
substance forms in the brain, in the spinal cord, and in
the higher sensory nerves a sort of putty’ (neuroglia),in
which the nervous elements are embedded” (p. 890 in
Virchow, 1856). This was the first use of the term neuroglia, which was then explained in greater detail in his
textbook (Virchow, 1858). Virchow’s illustration of the
subependymal glia is reproduced in Figure 1. His textbook also illustrates “connective cellular elements” from
white matter, some shown as nuclei without protoplasm
and others as small round or lentil-shaped cells. Presumably these were glial cells with cytoplasm either not
stained or incompletely stained. Because the brain’s connective substance seemed to differ in appearance and
consistency from that of other organs, Virchow felt the
need for a new word, and thus the term neuroglia or
Neruenkitp was born (Virchow, 1856, 1858).The name
survives, even as the original concept has radically
changed.
Received October 20, 1987; accepted November 9, 1987.
‘Neruenkitt has been translated as “nerve-glue” or “nerve-cement”by others.
But, for glue and cement the German language has Leirn, Klebstoff,and Zement.
In choosing Kitt Virchow seems t o have had in mind a stuff that, besides being
sticky, also has bulk and shape, yet is not stone hard. Hence, putty seems the
nearest English equivalent.
‘See footnote 1
HISTORY OF NEUROGLIA
3
Fig. 1. Virchow’s illustration of subependymal neuroglia. E, ependymal epithelium; v-w, blood vessel in “connective tissue”; N, nerve
fibers; ca, corpora amylacea (amyloid bodies; presumably fixation artifacts?). (From Virchow, 1858, Fig. 94.)
According to Ramon y Cajal (1909 and 1911) it was
Deiters (1865) who first identified cells in central nervous tissue that were not neurons. Through much of the
late 19th century the supposed connective tissue cells of
the central nervous system were referred to as “Deiters’
cells” (not to be confused with neurons of Deiters’ nucleus, as in today’s usage). Yet one must wonder whether
the identification of these cells has always been correct.
Deiters (1865)certainly had the right idea. He reasoned
that any cell that does not have an axon (more precisely,
a Hauptaxencylinderfortsatz)cannot be a nerve cell.
Among the illustrations in his posthumously published
book (Deiters, 1865),two cells have been labeled Bindegewebszellen, i.e., connective tissue cells. These are re-
produced in Figure 2. The question is, what are they,
really? I have shown these drawings to six neuroanatomists (some trained in the United States, some in Europe) without revealing the source or the author’s intent.
One of my consultants wondered whether they were glia
or neurons, all others concluded that they were nerve
cells of one sort or another. Since one of the two cells
(Fig. 2, right side) is said to come from white matter it
may be an oligodendrocyte, but the other, from the hypoglossal nucleus, may just as well be a neuron whose
axon either did not take the stain or is at this level of
resolution indistinguishable from its dendrites. The
point is, with the technique available to Deiters, neurons could have been mistaken for glia.
4
SOMJEN
Fig. 2. “Connective tissue” cells, according to Deiters. On the left
side, from hypoglossal nucleus; on the right (marked “ll”), from white
matter. (From Deiters, 1865, Plate 2.)
Perhaps Golgi (1885-1886) should be truly credited
with starting the modern study of glial cells. Golgi emphasized that of the many characteristics described by
his predecessors as distinguishing glia from neurons
only the one used by Deiters, the absence of a n axon, is
reliable. (The confusion around amacrine cells arose only
later). With his superior technique, Golgi could be justifiably confident in making this distinction. Actually, he
preferred the term “nervous prolongation” and reserved
“axis cylinder” to denote the long unbranched shaft of
what we call an axon. Thus, in Golgi’s vocabulary “type
2” cells (that is, interneurons with short, branched axons) have nervous prolongations but no axis cylinder,
while the nervous prolongations of “type 1cells” become
axis cylinders as they course distally from the perikaryon; but connective cells have no nervous prolongation at
all, by definition. For dendrites Golgi used the term
“protoplasmic prolongation.’’
LenhossBk (1891) quotes Golgi as reporting for the first
time the fibers that extend radially from ependymal
cells to the pial surface of embryonal spinal cords, but
he credits Nansen with the insight that Deiters’ cells
are actually derived from embryonal ependyma. (Glia
and Deiters’ cells were still used as synonyms in this
period). This interpretation, that ependyma is the progenitor of glia, led to a radical reappraisal of the nature
of glial tissue. For ependyma is ectodermal, that is to
say epithelial, and therefore glia too must, in essence,
be epithelium and not a connective tissue. The ependyma1 origin of glial cells was reaffirmed, among others,
by Ramon y Cajal (1913). Achucarro (1915) spoke of
“ependymal glia” and “autonomous glia” to emphasize
the close relation between the two. By “autonomous
glia” he meant mature glial cells that became detached
from the ependymal layer. That the fibers of embryonal
glia may guide the migration of developing neurons was
first suggested by His (1889).
Weigert (1895)started a short-lasting but lively debate
when he wrote that glial fibers were separate from glial
cell bodies. Perhaps in analogy with collagen fibers, he
thought that glial fibers were produced by, but did not
remain continuous with, the protoplasm of glial cell
bodies. Golgi and later Ramon y Cajal opposed this view;
they saw glial processes as extensions of the perikaryon.
Ramon y Cajal (1909) argued in some detail why glial
fibers cannot be collagenous. Held (1903) started another
controversy, by suggesting that glial fibers formed a
syncytial network. Ramon y Cajal, as is well known,
rejected all suggestions of the existence of syncytial continuity of cytoplasm, whether among nerve cells or glia,
and his doctrine of the strict separation of the cytoplasm
of adjacent cells prevailed.
In 1893 Andriezen distinguished fibrous glia, found
mainly in white matter, from protoplasmic glia, residing
mostly in the gray. But Andriezen (1893) believed that
the protoplasmic cell is of mesoblastic origin, while the
fibrous cell is ectodermal. Ramon y Cajal (1909, 1913)
adopted this classification but insisted that both fibrous
and protoplasmic types are ectodermal, and he attached
the name astrocyte to both (Fig. 3). Subsequently Ramon
HISTORY OF NEUROGLIA
5
Fig. 3. Protoplasmic astrocytes, as drawn by Ramon y Cajal (1913). pedicles, continuous with neuroglial processes; c, fine perivascular
A, astrocyte; B, neuron, probably with short axon; a,b, pericellular pedicle. Gold chloride stain.
y Cajal (1913) added to the then-known two major categories of cells, neurons and “legitimate” neuroglia, the
“third element” of the nervous system. Cells of this
“tercer elemento,” the adendritic or apolar cells, were
thought by him to be derived from mesoderm. Now it
may sometimes seem that Ramon y Cajal was never
wrong, yet his “third element” cells turned out to be
products of imperfect technique. As del Rio-Hortega
(1920, 1932, 1942) and Penfield (1924, 1932) demonstrated, the cells that seemed devoid of processes were
incompletely stained oligodendrocytes and microglial
cells (see also Glees, 1955).
Summing up the history of glial research up to this
time, Schaffer (1926) (best known for the collateral
branches of CA3 hippocampal cell axons that bear his
name) defined three periods: 1)Golgi’s period that led to
the recognition of multipolar glial cells, and also of their
intimate relationship to blood vessels; 2) Weigert’s period, best known for the study of fibrous glia; 3) Ramon
y Cajal’s period, leading to the distinctions of protoplasmic glia and the “third element.” To Schaffer’s three
epochs we could add the fourth, that of del Rio-Hortega,
crystallizing the still-accepted classification of glia
(Fig. 4).
Del Rio-Hortega (1920) introduced the term “microglia” to describe a new central nerve cell type that he
considered derived to be from mesodermal elements. But
already well before him, in a short communication to
the meeting of the Medico-Psychological Association in
London, read breathlessly by Dr. Clouston on behalf of
the “unavoidably absent” Robertson (1900), the existence of a new type of central nervous cell had been
announced. Robertson (1900) christened these “mesoglia” to emphasize their mesodermal origin. Ramon y
Cajal (1920) considered Robertson’s mesoglia and del
Rio-Hortega’s microglia one and the same, but Penfield
(1924) and del Rio-Hortega (1942) believed that Robertson’s cells corresponded to Rio-Hortega’s oligodendrocytes. We shall probably never know who was right. In
any event, for some time microglia were also called
Hortega’s cells by many authors.
To del Rio-Hortega (1920, 1932) we owe the first detailed, classical study of microglia. In his view these
cells are wandering histiocytes of mesodermal origin,
6
SOMJEN
Fig. 4. Del Rio-Hortega’s (1920) illustration of the four types of
interstitial cells in the human nervous tissue. A. Protoplasmic neuroglia from the gray matter. B: Neuroglia of the fibrous type from white
unlike “classical” glia, which is epithelial. He was also
the first to stain adequately and to define precisely oligodendrocytes, which he first called interfascicular glia
(Fig. 4) (del Rio-Hortega, 1920, 1933; Penfield, 1924,
1932).Schaffer (19261, who contributed to the description
of microglia and agreed that they are a class apart,
nonetheless believed them derived from neuroepithelium-that is, from the primitive ependyma. Ramon y
Cajal (1920) eventually came to accept the existence of
microglia as a separate class of cell, but not that of
oligodendroglia. The dispute is said to have led to a
matter. C: Microglia. D: Interfascicular glia, or oligodendrocytes, from
the white matter of the brain.
break in the relationship between Hortega and Ram6n
y Cajal, disciple and teacher.
Once glial cells had properly been differentiated from
neurons, the door was opened to speculation over their
functions. Virchow of course conceived of glia as simply
giving shape to the brain and holding its cells together.
But this limited view did not last.
According to Golgi (1885-18861, glial cells feed neurons. This was based on the following reasoning. Golgi
(1885-1886) denied that the dendrites (“protoplasmic
prolongations”) of nerve cells participated in nervous
HISTORY OF NEUROGLIA
7
Fig. 5 . Hortega’s microglia in action. Left In health. From del Rio- voracious monsters and are valuable assistants in cleaning the tissue
Hortega’s legend “the brain’s nerve cells have bodyguards which of whatever has damaged the nerve cells.” (From del Rio-Hortega,
extend their tentacles in every direction, and hold back whatever 1933.)
might be noxious.” Right: In a case of encephalitis the cells “resemble
signaling, but rather attributed to them the function of
supplying nutrients to the cell body and the axon. Since
glial cells seemed to have dendrites but no axon, he
concluded that they must serve as conveyors of nutrients. To support this notion, Golgi called attention to
the frequent intimate relationship of the endfeet of glial
processes with blood vessels on the one hand, and between “protoplasmatic prolongations” of glia and nerve
cells on the other. Glial cells thus seemed to be in the
exact position to supply nutrients to the “noble elements” of the brain, namely the nerve cells. The rarity
of contact of neuron dendrites with blood vessels reinforced this view.
In his great book, Ramon y Cajal(1909) asks the rhetorical question, what is the function of glia? His answer: No one knows. He explained this lack of understanding by pointing out that physiologists do not have
the tools with which to study glial cells directly. Ramon
y Cajal rejected Golgi’s nutritive theory. Nor did he like
much better Weigert’s notion that glia is passive and
simply fills the spaces where there are no neurons. Ramon y Cajal did agree that glial cells, which can divide,
proliferate to fill the gaps left by dying neurons, which
cannot divide. But he protested that this could hardly
be their sole role. Then, Ramon y Cajal quoted with
much favor a n idea advanced by his brother, that glial
cells and their processes serve to insulate nerve fibers.
Especially where many dendrites and unmyelinated axons cross each other’s path, it is important that each
should preserve its individual signal, and it is here that
glial fibers abound. To Ramon y Cajal, unlike Golgi, it
was evident that dendrites carry nerve impulses. Of
myelin, which appears only in higher animals, Ramon y
Cajal thought that it was a more perfect insulation than
glial cells can provide. But if myelin is better than glial
processes, then the glia in white matter seems redundant, and here Ramon y Cajal (1909) was at a loss to
explain its role.
While he could not think of a role for “legitimate” glia
in white matter, Ramon y Cajal(l913) believed that his
“third element” cells of central white matter and the
Schwann cells of peripheral nerves may be analogous.
After the re-definition of the third element as interfascicular oligodendroglia, del Rio-Hortega (1922, 1942)
8
SOMJEN
Fig. 6. Penfield‘s (1924) illustrations. Left: Oligodendroglia in cerebellar white matter, situated on a vessel. Right Microglia perivascular
satellite from cerebral cortex.
adopted the idea. Penfield (1924) reaffirmed it and
spelled the likely role of oligodendrocytes in the formation of myelin.
That glial cells remove dying neurons by phagocytosis
was first reported by Marinesco (1896). This was before
any one realized the difference between microglia and
other types of glia. Later microglial cells were, so to
speak, caught in the act of phagocytosis by del RioHortega (19331, whose illustration is reproduced in Figure 5 . The young Penfield (1924) studied microglia as
well as oligodendrocytes while working in the
Laboratory of Histopathology in Ramon y Cajal’s institute in Madrid (Fig. 6). He discussed microglia as wandering histiocyte scavengers, confirming that
“Stabchenzellen” (rod cells; celulas en bastoncito) and
“Gitterzellen” (reticulated cells; Gitter = grating or
fretwork) are transformed microglial cells in pathological material (del Rio-Hortega, 1920; Ramon y Cajal,
1920; Penfeld, 1924, 1932).
Nageotte (1910) described secretory granules in glial
cells and suggested that glia is a n endocrine gland.
Ramon y Cajal (1913) agreed that protoplasmic astrocytes resembled secretory cells. The idea was picked up
by Achucarro (19151, who considered glial processes to
be tubular structures. Secretions produced by glial cells
could be conveyed by these tubular extensions to the
blood vessels and there discharged into the blood stream.
The role of the adrenal gland in the visceral manifestations of emotional states was already well known. Achucarro (1915) speculated that endocrine secretions of glial
tissue could be a humoral link between central nervous
system and peripheral organs. As more and more neuroactive amines and peptides are found in various classes
of glial cells, the idea acquires potential contemporary
significance. Could messenger substances released from
glial endfeet be transported by capillary endothelial
cells, and if so, could these find their way in physiologically significant concentration to peripheral organs of
the body?
Especially remarkable is a paper by Lugaro (1907),
whose name is all but forgotten although he was frequently quoted by his contemporaries. Without a doubt,
his essay is long on inspiration if short on facts. It begins
with a critical review of the theories that preceded Lu-
garo’s, but then there follow intriguing original proposals. Lugaro adopted His’ (1889) suggestion that
embryonal glial cells guide the migration of developing
neurons, and he added the concept of chemotaxis as the
mechanism of guidance. Concerning the functions of
adult astrocytes, his central notion was that glial cells
keep the cerebral interstitial fluid habitable for neurons. Thus, Lugaro seems to have been the first to propose that perivascular glial endfeet serve as a detoxifying filter to screen out unwanted substances that might
enter from blood into brain. He also thought that glial
cells might remove toxic waste products of neuronal
metabolism. Even more surprisingly, Lugaro (1907)
pointed out that glial processes invest “nervous articulations” (read: synapses) and ventured the guess that
these might serve to “chemically split or take up” the
substances, by which one nerve cell excites another, to
terminate their action.
So there you have it. The questions linger. Is glia a
gland? Does it transport materials? Does it live in symbiosis with nerve cells? Does it assist their metabolism?
Does it prevent ephaptic interference by the currents of
action among neighboring neural processes? Does it terminate or otherwise modulate transmitter action a t synapses? Does it regulate the composition of interstitial
fluid? Does it have a role in the exchange between blood
and brain? Perhaps future volumes of this newborn journal will contain the answers.
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