Schwann Cells Electrically Excitable

Introduction to Glia

There are two major classes of cells in the brain - neurones and glia (Figure 1.1). The fundamental difference between these lies in their electrical excitability -neurones are electrically excitable cells whereas glia represent nonexcitable neural cells. Neurones are able to respond to external stimulation by generation of a plasmalemmal 'all-or-none' action potential, capable of propagating through the neuronal network, although not all neurones generate action potentials. Glia are unable to generate an action potential in their plasma membrane (although they are able to express voltage-gated channels). Glial cells are populous (as they account for ~90 per cent of all cells in the human brain) and diverse. In the central nervous system (CNS) they are represented by three types of cells of neural (i.e. ectodermal) origin, often referred to as 'macroglial cells' (which may also be properly called 'neuroglial cells'). These are the astrocytes, the oligodendrocytes and the ependymal cells. The ependymal cells form the walls of the ventricles in the brain and the central canal in the spinal cord. Ependymal cells are involved in production and movement of cerebrospinal fluid (CSF), in forming a separating layer between the CSF and CNS cellular compartments, and in exchange of substances between the two compartments. In addition to neuroglia, the umbrella term glia covers microglia, which are of non-neuronal (mesodermal) origin and originate from macrophages that invade the brain during early development and settle throughout the CNS. In the peripheral nervous system (PNS), the main class of glia is represented by Schwann cells, which enwrap and myelinate peripheral axons; other types of peripheral glia are satellite cells of sensory and sympathetic ganglia and glial cells of the enteric nervous system (ENS) of the gastrointestinal tract.

1.1 Founders of glial research: from Gabriel Valentin to Karl-Ludwig Schleich

The idea of the co-existence of active (excitable) and passive (non-excitable) elements in the brain was first promulgated in 1836 by the Swiss professor of

Neural Cells

Glia

Schwann cells

Astrocytes (~80%)

Ependymal cells (~5%)

Oligodendrocytes (~5%)

Figure 1.1 Neural cell types anatomy and physiology Gabriel Gustav Valentin (1810-1883), in the book Über den Verlauf und die letzten Enden der Nerven. The concept and term 'glia' was coined in 1858 by Rudolf Ludwig Karl Virchow (1821-1902, Figure 1.2), in his own commentary to the earlier paper 'Über das granulierte Ansehen der Wandungen der Gehirnventrikel' (published in the journal Allgemeine Zeitshrift fur Psychiatrie; Vol. 3, pp. 242-250), and elaborated in detail in his book, Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre. Virchow was one of the most influential pathologists of the 19th century - he was one of the originators of the cellular theory ('Omnis cellula e cellula') and of cellular pathology.

Virchow derived the term 'glia' from the Greek '7x1a' for something slimy and of sticky appearance (the root appeared in a form 7X0100- in writings of Semonides where it referred to 'oily sediment' used for taking baths; in works of Herodotus, for whom it meant 'gum'; and in plays of Aristophanes, who used it in a sense of 'slippery or knavish'. In Modern Greek, the root remains in the word '7X01«^', which means filthy and morally debased person.) Virchow contemplated glia as a 'nerve putty' in 1858 when he held a chair of pathological anatomy at Berlin University. He initially defined glia as a 'connective substance, which forms in the brain, in the spinal cord, and in the higher sensory nerves a sort of nervenkitt (neuroglia), in which the nervous system elements are embedded'; where 'nervenkitt' means 'neural putty'. For Virchow, glia was a true connective tissue, completely devoid of any cellular elements.

The first image of a neuroglial cell, the radial cell of the retina, was obtained by Heinrich Müller in 1851 - these are now known as retinal Müller cells. Several years later, these cells were also described in great detail by Max Schultze. In the beginning of 1860, Otto Deiters described stellate cells in white and grey matter, these cells closely resembling what we now know as astrocytes. Slightly

CELLULAEPATHOLOGIE

in ihrer Begründung auf physiologische und pathologische Gewebelehre, dargestellt

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Rudolf VIRCHOW, (1821-1902)

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Figure 1.2 Rudolf Virchow - father of glia; the frontispiece of his book Die Cellulai-pathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre (Berlin, Verlag von August Hirschfeld, 1858) is shown on the right

Camillo Golgi

Figure 1.3 Santiago Ramón y Cajal and Camillo Golgi. The bottom panel shows original images of glial cells drawn by Ramón y Cajal: 'Neuroglia of the superficial layers of the cerebrum; child of two months. Method of Golgi. A, B, [C], D, neuroglial cells of the plexiform layer; E, F, [G, H, K], R, neuroglial cells of the second and third layers; V, blood vessel; I, J, neuroglial cells with vascular [pedicles].' This figure was reproduced as Figure 697 in Textura and Figure 380 in Histologie. (Copyright Herederos de Santiago Ramón y Cajal)

Figure 1.3 Santiago Ramón y Cajal and Camillo Golgi. The bottom panel shows original images of glial cells drawn by Ramón y Cajal: 'Neuroglia of the superficial layers of the cerebrum; child of two months. Method of Golgi. A, B, [C], D, neuroglial cells of the plexiform layer; E, F, [G, H, K], R, neuroglial cells of the second and third layers; V, blood vessel; I, J, neuroglial cells with vascular [pedicles].' This figure was reproduced as Figure 697 in Textura and Figure 380 in Histologie. (Copyright Herederos de Santiago Ramón y Cajal)

later (1869), Jakob Henle published the first image of cellular networks formed by stellate cells (i.e. astrocytes) in both grey and white matter of the spinal cord. Further discoveries in the field of the cellular origin of glial cells resulted from the efforts of many prominent histologists (Figures 1.3 and 1.4), in particular Camillo Golgi (1843-1926), Santiago Ramón y Cajal (1852-1934), and Pio Del Rio Hortega (1882-1945). S. Ramón y Cajal was born on May 1,1852, in Aragon, Spain. In 1883 he was appointed Professor of Descriptive and General Anatomy at Valencia; in 1887 he was assumed a chair of in University of Barcelona and in 1892 he became Professor of Histology and Pathological Anatomy in Madrid.

Cajal Spinal Cord Anatomy

Figure 1.4 Morphological diversity and preponderance of glial cells in the brain as seen by Gustaf Magnus Retzius (1842-1919). Retzius was Professor of Histology at the Karolinska Institute in Stockholm from 1877. He investigated anatomy and histology of the brain, hearing organs and retina. The image shows a drawing from Retzius' book Biologische Untersuchungen (Stockholm: Samson and Wallin, 1890-1914), Vol. 6 (1894), Plate ii, Figure 5, where two neurones are marked with an arrow; the host of glial cells are stained by a silver impregnation method. (The image was kindly provided by Professor Helmut Kettenmann, MDC, Berlin)

Figure 1.4 Morphological diversity and preponderance of glial cells in the brain as seen by Gustaf Magnus Retzius (1842-1919). Retzius was Professor of Histology at the Karolinska Institute in Stockholm from 1877. He investigated anatomy and histology of the brain, hearing organs and retina. The image shows a drawing from Retzius' book Biologische Untersuchungen (Stockholm: Samson and Wallin, 1890-1914), Vol. 6 (1894), Plate ii, Figure 5, where two neurones are marked with an arrow; the host of glial cells are stained by a silver impregnation method. (The image was kindly provided by Professor Helmut Kettenmann, MDC, Berlin)

Ramón y Cajal was, and remains, one of the most prominent and influential neurohistologists, who described fine structure of various parts of the nervous system. He was the most important supporter of the neuronal doctrine of brain structure. He won the Nobel Prize in 1906 together with Camillo Golgi.

Camillo Golgi was born in Brescia on July 7, 1843. Most of his life he spent in Pavia, first as a medical student, and then as Extraordinary Professor of Histology, and from 1881 he assumed a chair for General Pathology. He supported the reticular theory of brain organization. Using various ingenious staining and microscopic techniques, Camillo Golgi discovered a huge diversity of glial cells in the brain, and found the contacts formed between glial cells and blood vessels, as well as describing cells located in closely aligned groups between nerve fibres - the first observation of oligodendrocytes. Further advances in morphological characterization of glia appeared after Golgi developed his famous 'black' (or silver nitrate) technique (la reazione nera) for staining of cells and subcellular structures, and when Ramón y Cajal invented the gold-chloride sublimate staining technique, which significantly improved microscopic visualization of cells (and neuroglial cells in particular) in brain tissues. Using these techniques Golgi, Cajal and many others were able to depict images of many types of glia in the nervous system (Figures 1.3, 1.5).

In 1893, Michael von Lenhossek proposed the term astrocyte (from the Greek for star, astro, and cell, cyte) to describe stellate glia, which gained universal acceptance within the next two decades. The name oligodendrocyte (from the Greek for few, oligo, branches, dendro, and cell, cyte) was coined slightly later, after Pio Del Rio-Hortega introduced the silver carbonate staining technique, which selectively labelled these cells (1921). It was also Del Rio-Hortega who proposed the term 'microglia' to characterize this distinct cellular population; he was one of the first to propose that microglia are of mesodermal origin and to understand that these cells can migrate and act as phagocytes.

The main peripheral glial element, the Schwann cell, was so called by Louis Antoine Ranvier (1871), following earlier discoveries of Robert Remak, who described the myelin sheath around peripheral nerve fibres (1838) and Theodor Schwann, who suggested that the myelin sheath was a product of specialized cells (1839).

At the end of 19th century several possible functional roles for glial cells were considered. Camillo Golgi, for example, believed that glial cells are mainly responsible for feeding neurones, by virtue of their processes contacting both blood vessels and nerve cells; this theory, however, was opposed by Santiago Ramón y Cajal. Another theory (proposed by Carl Weigert) considered glial cells as mere structural elements of the brain, which filled the space not occupied by neurones. Finally, Santiago Ramón y Cajal's brother, Pedro, considered astrocytes as insulators, which prevented undesirable spread of neuronal impulses.

The idea of active neuronal-glial interactions as a substrate for brain function was first voiced in 1894 by Carl Ludwig Schleich (1859-1922) in his book Schmerzlose Operationen (Figure 1.5). Incidentally, this happened in the same

Glial Cells The Brain

Carl Ludwig Schleich (1859-1922)

Figure 1.5 Carl Ludwig Schleich and the neuronal-glial hypothesis. Schleich was a pupil of Virchow and surgeon who introduced local anaesthesia into clinical practice. In 1894 he published a book Schmerzlose Operationen. Betäubung mit indifferenten Flüssigkeiten, Verlag Julius Springer, Berlin (the frontispiece of which is shown on the right upper panel). Apart from describing the principles of local anaesthesia, this also contained the first detailed essay on interactions in neuronal-glial networks as a substrate for brain function. Lower panels show original drawings from this book depicting intimate contacts between glial cells and neurones

Figure 1.5 Carl Ludwig Schleich and the neuronal-glial hypothesis. Schleich was a pupil of Virchow and surgeon who introduced local anaesthesia into clinical practice. In 1894 he published a book Schmerzlose Operationen. Betäubung mit indifferenten Flüssigkeiten, Verlag Julius Springer, Berlin (the frontispiece of which is shown on the right upper panel). Apart from describing the principles of local anaesthesia, this also contained the first detailed essay on interactions in neuronal-glial networks as a substrate for brain function. Lower panels show original drawings from this book depicting intimate contacts between glial cells and neurones

Wilhelm Gottfried von Waldeyer (1836-1921)

Sigmund Exner (1846-1826)

Figure 1.6 The neuronal doctrine and its founders. Wilhelm Gottfried von Waldeyer was a professor of Anatomy in Berlin from 1883; where he made numerous important contributions to general histology (in particular he introduced the term 'chromosome'), and he also authored the term 'neurone' (1891). Sigmund Exner held a Chair in Physiology in Vienna University from 1891; and in 1894 he published a book (Entwurf zur physiologischen Erklärung der psychishen Erscheinungen. 1894), which described the neuronal doctrine of brain organization. The right panel displays an original scheme from his book, which shows neuronal networks connected by synapses year as the 'neuronal' doctrine was promulgated by Sigmund Exner (1846-1926) in the book Entwurf zur physiologischen Erklärung der psychishen Erscheinungen, (Berlin, 1894; Figure 1.6), and only three years after the term 'neurone' was coined by Wilhelm Gottfried von Waldeyer (1891, Figure 1.6). Schleich believed that glia and neurones were equal players and both acted as active cellular elements of the brain. He thought that glial cells represented the general inhibitory mechanism of the brain. According to Schleich, neuronal excitation is transmitted from neurone to neurone through intercellular gaps, and these interneuronal gaps are filled with glial cells, which are the anatomical substrate for controlling network excitation/inhibition. He postulated that the constantly changing volume of glial cells represents the mechanism for control - swollen glial cells inhibit neuronal communication, and impulse propagation is facilitated when glia shrink.

1.2 Beginning of the modern era

The modern era in glial physiology began with two seminal discoveries made in the mid 1960s, when Steven Kuffler, John Nicolls and Richard Orkand (1966) demonstrated electrical coupling between glial cells, and Milton Brightman and Tom Reese (1969) identified structures connecting glial networks, which we know now as gap junctions. Nonetheless, for the following two decades, glial cells were still regarded as passive elements of the CNS, bearing mostly supportive and nutritional roles. The advent of modern physiological techniques, most notably those of the patch-clamp and fluorescent calcium dyes, has dramatically changed this image of glia as 'silent' brain cells.

1.3 Changing concepts: Glia express molecules of excitation

The first breakthrough discovery was made in 1984 when groups led by Helmut Kettenmann and Harold Kimelberg discovered glutamate and GABA receptors in cultured astrocytes and oligodendrocytes. Several years later, in 1990 Ann Cornell-Bell and Steve Finkbeiner found that astroglial cells are capable of long-distance communication by means of propagating calcium waves. These calcium waves can be initiated by stimulation of various neurotransmitter receptors in the astroglial plasma membrane.

Detailed analysis of the expression of these receptors performed during the last two decades demonstrated that glial cells, and especially astrocytes, are capable of expressing practically every type of neurotransmitter receptor known so far. Moreover, glial cells were found to possess a multitude of ion channels, which can be activated by various extracellular and intracellular stimuli. Thus, glial cells are endowed with proper tools to detect the activity of neighbouring neurones.

1.4 Glia and neurones in dialogue

Neurotransmitter receptors and ion channels expressed in glial cells turned out to be truly operational. It has now been shown in numerous experiments on various regions of the CNS and PNS that neuronal activity triggers membrane currents and/or cytosolic calcium signals in glial cells closely associated with neuronal synaptic contacts.

Finally, glial cells can also feed signals back to neurones, as they are able to secrete neurotransmitters, such as glutamate and ATP. This discovery resulted from the efforts of several research groups, and has led to the concept of much closer interactions between two circuits, neuronal and glial, which communicate via both chemical and electrical synapses.

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  • antje
    Are schwann cells exiteable?
    3 years ago

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