appear as sheets, as in the fenestrated elastic lamellae of the aortic wall.
tissues often have thinner fibrils than mature tissues. Corneal stroma
Elastin-rich structures stretch easily with almost perfect recoil, although
fibrils are of uniform and thin diameter, whereas tendon fibrils may be
they tend to calcify with age and lose elasticity. Elastin is highly resistant
up to 20 times thicker and quite variable. Tissues in which the fibrils
to attack by acid and alkali, even at high temperatures.
are subject to high tensile loading tend to have thicker fibrils. Thick
fibrils are composites of uniform thin fibrils with a diameter of 8–12 nm.
Interfibrillar matrix
The fibrils themselves are relatively flexible, but when mineralized (as
in bone) or surrounded by high concentrations of proteog lycan (as in
Glycosaminoglycans
cartilage), the resulting fibre-reinforced composite materials are rigid.
Fresh type I collagen fibres are tightly packed assemblies of parallel The structural soluble polymers characteristic of the extracellular matrix
fibrils and are white and glistening. They form variably wavy (crimped) are the acidic glycosaminoglycans, which are unbranched chains of
bundles of various sizes that are generally visible at the light microscope repeating disaccharide units, each unit carrying one or more negatively
level. The component fibres may leave one bundle and interweave with charged groups (carboxylate or sulphate esters, or both). The anionic
others. In some situations, collagen fibrils are laid down in precise geo- charge is balanced by cations (Na+, K+, etc.) in the interstitial fluid. Their
metrical patterns, in which successive layers alternate in direction, e.g. polyanionic character endows the glycosaminoglycans with high
corneal stroma, where the high degree of order is essential for transpar- osmotic activity, which helps to keep the fibrils apart, confers stiffness


Connective and supporting tissues
39
2
RETPAHC
on the porous gel that they collectively create, and gives the tissue a Tenascin
varying degree of basophilia. Glycosaminoglycans are named according Tenascin is large glycoprotein composed of six subunits that are joined
to the tissues in which they were first found, e.g. hyaluronan (vitreous at one end to form a structure that resembles the spokes of a wheel.
body), chondroitins (cartilage), dermatan (skin), keratan (cornea), There is a family of tenascin molecules, generated by alternative splicing
heparan (liver). This terminology is no longer relevant, as most gly- of the tenascin gene transcript. Tenascin is abundant in embryonic
cosaminoglycans are very widely distributed, whereas, conversely, some tissues but its distribution is restricted in the adult. It appears to be
corneas contain little or no keratan sulphate. Of the glycosaminogly- important in guiding cell migration and axonal growth in early develop-
cans, all except hyaluronan have short protein cores and are highly ment: it may either promote or inhibit these activities, depending on
variable in their carbohydrate side-chain structure. the cell type and tenascin isoform.
Hyaluronan
Hyaluronan was formerly called hyaluronic acid (or hyaluronate, as CLASSIFICATION OF CONNECTIVE TISSUES
only the salt exists at physiological pH). It is a very large, highly hydrated
molecule (25,000 kDa). Hyaluronan is found in all extracellular matri-
Connective and supporting tissues differ considerably in appearance,
ces and in most tissues, and is a prominent component of embryonic
consistency and composition in different regions. These differences
and developing tissues.
reflect local functional requirements and are related to the predomi-
Hyaluronan is important in the aggregation of proteoglycans and
nance of the cell types; the concentration, arrangement and types of
link proteins that possess specific hyaluronan binding sites (e.g.
fibre; and the characteristics of the interfibrillar matrix. On these
laminin). Indeed, the very large aggregates that are formed may be the
bases, general connective tissues can be classified into irregular and
essential compression-resisting units in cartilage. Hyaluronan also


regular types, according to the degree of orientation of their fibrous
forms very viscous solutions, which are probably the major lubricants
components.
in synovial joints. Because of its ability to bind water, it is often present
in semi-rigid structures (e.g. vitreous humour in the eye), where it
cooperates with sparse but regular meshworks of thin collagen fibrils. Irregular connective tissues
Proteoglycans
Irregular connective tissues can be further subdivided into loose, dense
Proteoglycans have been classified according to the size of their protein and adipose connective tissue.
core; their nomenclature is under review. The same core protein can
bear different glycosaminoglycan side chains in different tissues. The Loose (areolar) connective tissue
functions of many proteoglycans are poorly understood. Some of the Loose connective tissue is the most generalized form and is extensively
better-known proteoglycans are: aggrecan in cartilage, perlecan in basal distributed. Its chief function is to bind structures together, while still
laminae, decorin associated with fibroblasts in collagen fibril assembly, allowing a considerable amount of movement to take place. It consti-
and syndecan in embryonic tissues. tutes the submucosa in the digestive tract and other viscera lined by
mucosae, and the subcutaneous tissue in regions where this is devoid
Adhesive glycoproteins
of fat (e.g. eyelids, penis, scrotum and labia), and it connects muscles,
These proteins include molecules that mediate adhesion between cells vessels and nerves with surrounding structures. It is present in the inte-
and the extracellular matrix, often in association with collagens, proteo- rior of organs, where it binds together the lobes and lobules of glands,
glycans or other matrix components. All of them are glycosylated and forms the supporting layer (lamina propria) of mucosal epithelia and
they are, therefore, glycoproteins. General connective tissue contains the vascular endothelia, and lies within and between fascicles of muscle
well-known families of fibronectins (and osteonectin in bone), lam- and nerve fibres.
inins and tenascins; there is a rapidly growing list of other glycoproteins Loose connective tissue consists of a meshwork of thin collagen and


associated with extracellular adhesion (Pollard et al 2008). They possess elastin fibres interlacing in all directions (see Fig. 2.13) to give a measure
binding sites for other extracellular matrix molecules and for cell adhe- of both elasticity and tensile strength. The large meshes contain the soft,
sion molecules, especially the integrins; in this way they enable cells semi-fluid interfibrillar matrix or ground substance, and different con-
selectively to adhere to and migrate through, appropriate matrix struc- nective tissue cells, which are scattered along the fibres or in the meshes.
tures (reviewed in Jacquemet et al (2013)). They also function as signal- It also contains adipocytes, usually in small groups, and particularly
ling molecules, which are detected by cell surface receptors and initiate around blood vessels.
changes within the cytoplasm (e.g. to promote the formation of A variant of loose connective tissue occurs in the choroid and the
hemidesmosomes or other areas of strong adhesion; reorganize the sclera of the eye, where large numbers of pigment cells (melanocytes)
cytoskeleton; and promote or inhibit locomotion and cell division). are also present.
Fibronectin Dense irregular connective tissue
Fibronectin is a large glycoprotein consisting of a dimer joined by Dense irregular connective tissue is found in regions that are under
disulphide links. Each subunit is composed of a string of large repetitive considerable mechanical stress and where protection is given to
domains linked by flexible regions. Fibronectin subunits have binding ensheathed organs. The matrix is relatively acellular and contains a high
sites for collagen, heparin and cell surface receptors, especially integrins, proportion of collagen fibres organized into thick bundles interweaving
and so can promote adhesion between all these elements. In connective in three dimensions and imparting considerable strength. There are few
tissues, the molecules are able to bind to cell surfaces in an orderly active fibroblasts, which are usually flattened with heterochromatic
fashion, to form short fibronectin filaments. The liver secretes a related nuclei. Dense irregular connective tissue occurs in: the reticular layer of
protein, plasma fibronectin, into the circulation. The selective adhesion the dermis; the superficial connective tissue sheaths of muscle and


of different cell types to the matrix during development and in postna- nerves, and the adventitia of large blood vessels; and the capsules of
tal life is mediated by numerous isoforms of fibronectin generated by various glands and organs (e.g. testis, sclera of the eye, periostea and
alternative splicing. Isoforms found in embryonic tissues are also perichondria).
expressed during wound repair, when they facilitate tissue proliferation
and cell movements; the adult form is re-expressed once repair is Adipose tissue
complete. A few adipocytes occur in loose connective tissue in most parts of the
body. However, they constitute the principal component of adipose
laminin tissue (see Fig. 2.11), where they are embedded in a vascular loose con-
Laminin is a large (850 kDa) flexible molecule composed of three nective tissue, usually divided into lobules by stronger fibrous septa
polypeptide chains (designated α, β and γ). There are many isoforms carrying the larger blood vessels. Adipose tissue only occurs in certain
of the different chains, and at least 18 types of laminin. The prototypical regions. In particular it is found: in subcutaneous tissue; in the mesenter-
molecule has a cruciform shape, in which the terminal two-thirds are ies and omenta; in the female breast; in bone marrow; as retro-orbital
wound round each other to form the stem of a cross, and the shorter fat behind the eyeball; around the kidneys; deep to the plantar skin of
free ends form the upright and transverse members. Laminin bears the foot; and as localized pads in the synovial membrane of many
binding sites for other extracellular matrix molecules such as heparan joints. Its distribution in subcutaneous tissue shows characteristic age
sulphate, type IV collagen and entactin, and also for laminin receptor and sex differences. Fat deposits serve as energy stores, sources of meta-
molecules (integrins) situated in cell plasma membranes. Laminin mol- bolic lipids, thermal insulation (subcutaneous fat) and mechanical
ecules can assemble themselves into flat regular meshworks, e.g. in the shock-absorbers (e.g. soles of the feet, palms of the hands, gluteal
basal lamina. region and synovial membranes).


INTEgRATINg CEllS INTO TISSuES
40
1
NOITCES
Mucosa
Epithelium
Lamina propria
Muscularis mucosae
Muscularis
externa
Submucosa
Serosa
Fig. 2.15 Dense regular connective tissue in a tendon. Thick parallel Duct of extrinsic
gland or organ
bundles of type I collagen (here stained pink) give tendon its white colour
in life. The elongated nuclei of inactive fibroblasts (tendon cells) are visible
between collagen bundles.
Submucosal gland
Regular connective tissues Fig. 2.16 A generalized mucosa and supporting tissues. For details and
variations, see text.
Regular connective tissues include highly fibrous tissues in which fibres
are regularly orientated, either to form sheets such as fasciae and
foci of stratified squamous metaplasia in response to irritants in ciga-
aponeuroses, or as thicker bundles such as ligaments or tendons (Fig.
rette smoke. Mesenchymal (osseous) metaplasia can occur, for example,
2.15). The direction of the fibres within these structures is related to
in the fibrous connective tissue of muscles subjected to repeated
the stresses that they undergo: fibrous bundles display considerable
damage, where trabeculi of bone develop. It is thought that stem cells
interweaving, even within tendons, which increases their structural sta-
(rather than the differentiated cells) in the affected tissue respond to
bility and resilience.
changes in their environment by altering their differentiation pathway,
The fibroblasts that secrete the fibres may eventually become trapped
a process that may be reversible if the stimulus is removed.
within the fibrous structure, where they become compressed, relatively
inactive cells with stellate profiles and small heterochromatic nuclei;
these cells are called tendon cells. Fibroblasts on the external surface MUCOSA (MUCOUS MEMBRANE)
may be active in continued fibre formation and they constitute a pool
of cells available for repair of injured tissue.
A mucosa or mucous membrane (Fig 2.16) lines many internal hollow
Although regular connective tissue is predominantly collagenous,
organs in which the inner surfaces are moistened by mucus, such as the
some ligaments contain significant amounts of elastin, e.g. the liga-


intestines, conducting portions of the airway, and the genital and
menta flava of the vertebral laminae and the vocal folds. The collagen
urinary tracts. A mucosa proper consists of an epithelial lining, which
fibres may form precise geometrical patterns, as in the cornea.
may have the ducts of mucosal, submucosal or extrinsic glands opening
on to its surface, an underlying loose connective tissue, the lamina
Mucoid tissue
propria, and a thin layer of smooth muscle, the muscularis mucosae.
This last layer either may be absent from some mucosae, or may be
Mucoid tissue is found chiefly as a stage in the development of connec- replaced by a layer of elastic fibres. The term mucous membrane reflects
tive tissue from mesenchyme. It exists in Wharton’s jelly, which forms the fact that these tissues can all be peeled away as a sheet or membrane
the bulk of the umbilical cord, and consists substantially of extracellular from underlying structures; the plane of separation occurs along the
matrix, largely made up of hydrated mucoid material and a fine mesh- muscularis mucosae.
work of collagen fibres, in which nucleated, fibroblast-like cells with Submucosa is a layer of supporting connective tissue that usually lies
branching processes are found. Fibres are usually rare in typical mucoid below the muscularis mucosae. It may contain mucous or seromucous
tissue, although the full-term umbilical cord contains perivascular col- submucosal glands. Inflammation of the viscera involves, primarily, the
lagen fibres. Postnatally, mucoid tissue is seen in the pulp of a develop- connective tissues of the submucosa and lamina propria, and is char-
ing tooth, the vitreous body of the eye (a persistent form of mucoid acterised by dilated vessels, oedema, and accumulations of extravasated
tissue that contains few fibres or cells) and the nucleus pulposus of the immune defence cells. Most mucosae are also supported by one or more
intervertebral disc. layers of smooth muscle, the muscularis externa. Contraction of this
muscle may constrict the mucosal lumen (e.g. in the airway) or, where


there are two or more muscle layers orientated in opposing directions
TRANSDIFFERENTIATION AND METAPLASIA
(e.g. in the intestines), cause peristaltic movement of the viscus and the
contents of its lumen. The outer surface of the muscle may be covered
Transitions occur between populations of cells forming an epithelium by a serosa or, where the structure is retroperitoneal or passes through
(sheets of polarized cells) and mesenchymal types (where the cells lack the pelvic floor, by a connective tissue adventitia.
polarity) during normal development (see Thiery et al (2009)). In post-
natal life, most well-described transitions between morphologically dif-
ferent cell types do not cross an epithelial–mesenchymal boundary but MUCUS
are transitions between types of epithelial cell or, less frequently,
between mesenchymal (connective tissue) cell types. Most instances Mucus is a viscous suspension of complex glycoproteins (mucins) of
of such transdifferentiation (metaplasia, see Commentary 1.4) are various kinds, and is secreted by scattered individual epithelial (goblet)
adaptive, to changing environmental conditions or trauma, and almost cells, a secretory surface epithelium (e.g. the stomach lining) or mucous
all are pathological; the altered cells are termed metaplastic. A very and seromucous glands. The precise composition of the mucus varies
common and physiologically normal example is the squamous meta- with the tissue and secretory cells that produce it. All mucins consist of
plasia of columnar secretory epithelium of the distal endocervical canal, filamentous core proteins to which are attached carbohydrate chains,
when exposed to the hormonally stimulated vaginal environment. usually branched; salivary mucus contains nearly 600 chains. Carbohy-
Gastric metaplasia of the lower oesophagus may occur when chronic drate residues include glucose, fucose, galactose and N-acetylglucosamine
reflux of gastric juices exposes its stratified squamous epithelial lining (sialic acid). The terminals of some carbohydrate chains are identical
to acid, and the original epithelium is replaced by a mucus-secreting to the blood group antigens of the ABO group in the majority of the


columnar epithelium typical of the stomach (Barrett’s oesophagus); this population (secretors, bearing the secretor gene Se), and can be detected
is pathological and susceptible to malignant change. Similarly, the res- in salivary mucus by means of appropriate clinical tests. The long poly-
piratory epithelium (see Fig. 2.2D) of the upper airway often develops meric carbohydrate chains bind water and protect surfaces against


41
2
RETPAHC
Key references
drying; they also provide good lubricating properties. In concentrated
FASCIA
form, mucins form viscous layers that protect the underlying tissues
against damage.
Synthesis of mucus starts in the rough endoplasmic reticulum. It is Fascia is a generic term applied to sheaths, sheets or other dissectible
then passed to the Golgi complex, where it is conjugated with sulphated masses of connective tissue that are large enough to be visible to the
carbohydrates to form the glycoprotein, mucinogen, and this is exported unaided eye. The terms superficial fascia and deep fascia, widely used
in small, dense, membrane-bound vesicles that swell as they approach to describe the connective tissue between the skin and underlying
the cell surface, with which they fuse before releasing their contents. muscle, and the connective tissue surrounding muscles, viscera and
related structures, respectively, are no longer included in the Terminolo-
gia Anatomica, although they remain in common usage in the English
SEROSA (SEROUS MEMBRANE)
language. Tela subcutanea, hypodermis and subcutaneous tissue are
the recommended synonymous terms that replace superficial fascia.
Serosa consists of a single layer of squamous mesothelial cells, express- Deeper-lying condensations of connective tissue have been defined
ing keratin intermediate filaments, supported by an underlying layer of according to their location, e.g. investing muscles (fascia musculorum)
loose connective tissue that contains numerous blood and lymphatic or viscera (fascia visceralis). Loosely packed connective tissue surrounds
vessels. Serosa lines the pleural, pericardial and peritoneal cavities, and peripheral nerves, blood and lymph vessels as they pass between
covers the external surfaces of organs lying within those cavities and, in other structures, often linking them together as neurovascular bundles.
the abdomen, the mesenteries that envelop them. A potential space, Some large vessels, e.g. the common carotid and femoral arteries, are
filled with a small amount of protein-containing serous fluid – largely invested by a dense connective tissue sheath that may be functionally
an exudate of interstitial fluid – exists between the outer parietal and significant, aiding venous return by approximating large veins to pulsat-
the inner visceral layers of the serosa. ing arteries.
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Immunol 32:478–85.
Pan X, Hobbs RP, Coulombe PA 2012 The expanding significance of keratin
A discussion of recent advances in understanding the recruitment of mast
intermediate filaments in normal and diseased epithelia. Curr Opin Cell
cells to tissues.
Biol 25:1–10.
Duffield JS 2012 The elusive source of myofibroblasts: problem solved? Nat A discussion of the current understanding of the keratin intermediate
Med 18:1178–80. filament family, specific to epithelia, and the roles of keratins in epithelial
A review of recent evidence for a perivascular cell (pericyte) origin for functions and selected diseases.
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Pollard TD, Earnshaw WC, Lippincott-Schwartz J 2008 Cell Biology, 2nd ed.
Frenzel L, Hermine O 2013 Mast cells and inflammation. Joint Bone Spine Philadelphia: Elsevier, Saunders; Ch. 29 Extracellular matrix molecules,
80:141–5. pp. 531–52.
A description of the role of mast cells in inflammatory processes and A comprehensive text on the molecular structures and functions of matrix
prospects for therapeutic intervention in inflammatory diseases. molecules.
Hassan M, Latif N, Yacoub M 2012 Adipose tissue: friend or foe? Nature Rev Thiery JP, Acloque H, Huang RYJ et al 2009 Epithelial–mesenchymal transi-
Cardiol 9:689–702. tions in development and disease. Cell 139:871–90.
A review of the status of adipose tissue, its structural and functional A description of these processes in normal development and the contribution
variations and roles in health and disease. of epithelial–mesenchymal transitions to carcinoma progression and
metastasis.
Hinz B, Phan SH, Thannickal VJ et al 2012 Recent developments in myofi-


broblast biology. Am J Path 180:1340–55. Wolf K, Friedl P 2011 Extracellular matrix determinants of proteolytic and
A review of recent work on myofibroblasts, their origins, molecular non-proteolytic cell migration. Trends Cell Biol 21:736–44.
regulation of differentiation from precursor cells and roles in organ-specific A review of cell migration through extracellular matrices in wound healing
fibrotic disease processes. and pathological processes, using proteolytic and other mechanisms.
McAnulty RJ 2007 Fibroblasts and myofibroblasts: their source, function and
role in disease. Int J Biochem Cell Biol 39:666–71.


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one step back. Trends in Mol Med 16:203–9. trafficking in 3D cell migration. Curr Opin Cell Biol 25:1–6.
Bischoff SC 2007 Role of mast cells in allergic and non-allergic immune McAnulty RJ 2007 Fibroblasts and myofibroblasts: their source, function and
responses: comparison of human and murine data. Nat Rev Immunol role in disease. Int J Biochem Cell Biol 39:666–71.
7:93–104. A review of the biology of connective tissue fibroblasts and related
Blanpain C, Horsley V, Fuchs E 2007 Epithelial stem cells: turning over new mesenchymal cells.
leaves. Cell 128:445–8. Mott JD, Werb Z 2004 Regulation of matrix biology by matrix metallopro-
Collington SJ, Williams TJ, Weller CL 2011 Innate immune cell trafficking: teinases. Curr Opin Cell Biol 16:558–64.
mechanisms underlying the localisation of mast cells in tissues. Trends Pan X, Hobbs RP, Coulombe PA 2012 The expanding significance of keratin
Immunol 32:478–85. intermediate filaments in normal and diseased epithelia. Curr Opin Cell
A discussion of recent advances in understanding the recruitment of mast Biol 25:1–10.
cells to tissues. A discussion of the current understanding of the keratin intermediate
Duffield JS 2012 The elusive source of myofibroblasts: problem solved? Nat filament family, specific to epithelia, and the roles of keratins in epithelial
Med 18:1178–80. functions and selected diseases.
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myofibroblasts and fibrotic tissue in a number of disease states. Philadelphia: Elsevier, Saunders; Ch. 29 Extracellular matrix molecules,
Even-Ram S, Yamada KM 2005 Cell migration in 3D matrix. Curr Opin Cell pp. 531–52.
Biol 17:524–32. A comprehensive text on the molecular structures and functions of matrix
molecules.
Frenzel L, Hermine O 2013 Mast cells and inflammation. Joint Bone Spine
80:141–5. Ren G, Chen X, Dong F et al 2012 Concise review: mesenchymal stem cells
A description of the role of mast cells in inflammatory processes and and translational medicine: emerging issues. Stem Cells Transl Med
prospects for therapeutic intervention in inflammatory diseases. 1:51–8.
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Cardiol 9:689–702. A description of these processes in normal development and the contribution
A review of the status of adipose tissue, its structural and functional of epithelial–mesenchymal transitions to carcinoma progression and
variations and roles in health and disease. metastasis.
Hinz B, Phan SH, Thannickal VJ et al 2012 Recent developments in myofi- Trayhurn P, Wood IS 2004 Adipokines: inflammation and the pleiotropic
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A review of recent work on myofibroblasts, their origins, molecular Wolf K, Friedl P 2011 Extracellular matrix determinants of proteolytic and
regulation of differentiation from precursor cells and roles in organ-specific non-proteolytic cell migration. Trends Cell Biol 21:736–44.
fibrotic disease processes. A review of cell migration through extracellular matrices in wound healing
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42
1
NOITCES
CHAPTER
3
Nervous system
The nervous system has two major divisions, the central nervous system with neurones in many different ways; their two-way communication
(CNS) and the peripheral nervous system (PNS). The CNS consists of is essential for normal brain activity.
the brain, spinal cord, optic nerve and retina, and contains the majority It was thought for many years that glia outnumbered neurones by
of neuronal cell bodies. The PNS includes all nervous tissue outside the 10 times in the CNS, but recent studies using the isotropic fractionator
CNS and consists of the cranial and spinal nerves, the peripheral auto- method have challenged that popular view, suggesting instead that the
nomic nervous system (ANS) and the special senses (taste, olfaction, two cell populations are rather similar in size (Azevedo et al 2009). That
vision, hearing and balance). It is composed mainly of the axons of said, the glia : neurone ratio has been reported to be as high as 17 : 1 in
sensory and motor neurones that pass between the CNS and the body. the thalamus (Pakkenberg and Gundersen 1988).
The ANS is subdivided into sympathetic and parasympathetic compo- The glial population in the CNS consists of microglia and macroglia;
nents. It consists of neurones that innervate secretory glands and cardiac the latter are subdivided into oligodendrocytes and astrocytes. The
and smooth muscle, and is concerned primarily with control of the principal glial cell in the PNS is the Schwann cell. Satellite cells sur-
internal environment. Neurones in the wall of the gastrointestinal tract round each neuronal soma in ganglia.
form the enteric nervous system (ENS) and are capable of sustaining For further reading on the nervous system, see Finger (2001), Kandel
local reflex activity that is independent of the CNS. The ENS contains et al (2012), Kettenmann and Ransom (2012), Levitan and Kaczmarek
as many intrinsic neurones in its ganglia as the entire spinal cord and (2001), Nicholls et al (2011) and Squire et al (2012).
is often considered as a third division of the nervous system (Gershon
1998).
NEURONES


In the CNS, the cell bodies of neurones are often grouped together
in discrete areas termed nuclei, or they may form more extensive layers
or masses of cells; collectively they constitute the grey matter. Neuronal Most of the neurones in the CNS are either clustered into nuclei,
dendrites and synaptic contacts are mostly confined to areas of grey columns or layers, or dispersed within grey matter. Neurones in the PNS
matter and form part of its meshwork of neuronal and glial processes, are confined to ganglia. Irrespective of location, neurones share many
termed the neuropil. Their axons join bundles of nerve fibres that tend general features, which are discussed here in the context of central
to be grouped separately to form tracts. In the spinal cord, cerebellum, neurones. Special characteristics of ganglionic neurones and their adja-
cerebral cortices and some other areas, concentrations of tracts consti- cent tissues are discussed on page 57.
tute the white matter, so called because the axons are often ensheathed Neurones exhibit great variability in their size (cell bodies range
in lipid-rich sheaths of myelin, which is white when fresh (Fig. 3.1; see from 5 to 100 µm diameter) and shape (Spruston 2008). Their surface
Fig. 16.9). areas are extensive because most neurones display numerous branched
The PNS is composed of the efferent axons (fibres) of motor neu- cell processes. They usually have a rounded or polygonal cell body
rones situated inside the CNS, and the cell bodies of sensory neurones (perikaryon or soma). This is a central mass of cytoplasm that encloses
(grouped together as ganglia) and their afferent processes. Sensory cells a nucleus and gives off long, branched extensions with which most
in dorsal root ganglia give off both centrally and peripherally directed intercellular contacts are made. Typically, one of these processes, the
processes; there are no synapses on their cell bodies. Also included are axon, is much longer than the others, the dendrites (Fig. 3.2). Gener-
ganglionic neurones of the ANS, which receive synaptic contacts from ally, dendrites conduct electrical signals towards a soma whereas axons


the peripheral fibres of preganglionic autonomic neurones whose cell conduct impulses away from it.
bodies lie within the CNS. For further details of the organization of the Neurones can be classified according to the number and arrange-
nervous system, see Chapter 16. ment of their processes (Bota and Swanson 2007). Multipolar neurones
When the neural tube is formed during prenatal development (Sanes (Fig. 3.3) are common; they have an extensive dendritic tree that arises
et al 2011), its walls thicken greatly but do not completely obliterate either from a single primary dendrite or directly from the soma, and a
the cavity within. The latter remains in the spinal cord as the narrow single axon. Bipolar neurones, which typify neurones of the special
central canal and becomes greatly expanded in the brain to form a series sensory systems, have only a single dendrite that emerges from the soma
of interconnected cavities called the ventricular system. In the fore- and opposite the axonal pole. Unipolar neurones, which transmit general
hindbrains, parts of the neural tube roof do not generate neurones but sensation, e.g. dorsal root ganglion neurones, have a single short process
become thin, folded sheets of secretory tissue, which are invaded by that bifurcates into a peripheral and a central process. This arrangement
blood vessels and are called the choroid plexuses. The latter secrete arises by the fusion of the proximal axonal and dendritic processes of
cerebrospinal fluid (CSF), which fills the ventricles and subarachnoid a bipolar neurone during development, and so such neurones may also
spaces, and penetrates the intercellular spaces of the brain and spinal be termed pseudounipolar. Neurones may also be classified according
cord to create their interstitial fluid. The CNS has a rich blood supply, to whether their axons terminate locally on other neurones (interneu-
which is essential to sustain its high metabolic rate. The blood–brain rones), or transmit impulses over long distances, often to distinct ter-
barrier places considerable restrictions on the substances that are able ritories via defined tracts (projection neurones).
to diffuse from the blood stream into the neuropil. Neurones are postmitotic cells and, with few exceptions, they are not


Neurones encode information, conduct it over considerable dis- replaced when lost.
tances, and then transmit it to other neurones or to various non-neural
targets such as muscle cells. The propagation of this information within
the nervous system depends on rapid electrical signals, the action SOMA
potentials. Transmission to other cells is mediated by secretion of neu-
rotransmitters at special junctions, either with other neurones (syn- The plasma membrane of the soma is generally unmyelinated and
apses), or with cells outside the nervous system, e.g. muscle cells at is contacted by both inhibitory and excitatory axosomatic synapses;
neuromuscular junctions, gland cells or adipose tissue, and causes very occasionally, somasomatic and dendrosomatic contacts may be
changes in the behaviour of the target cells. made. The non-synaptic surface may contain gap junctions and is partly
The nervous system contains large populations of non-neuronal covered by either astrocytic or satellite oligodendrocyte processes.
cells, termed neuroglia or glia. These cells do not generate action poten- The cytoplasm of a typical soma (see Fig. 3.2) is rich in rough and
tials, but convey information encoded as transient changes in intracel- smooth endoplasmic reticulum and free polyribosomes, indicating
lular calcium concentration, termed calcium signalling. Glia interact a high level of protein synthetic activity. Free polyribosomes often


Nervous system
42.e1
3
RETPAHC
WM
GM
Fig. 3.1 A section through the human cerebellum stained to show the
arrangement in the brain of the central white matter (WM, deep pink) and
the highly folded outer grey matter (GM). In the cerebellum, GM consists
of an inner granular layer of tightly packed small neurones (blue) and an
outermost molecular layer (pale pink), where neuronal processes make
synaptic contacts. (Courtesy of Mr Peter Helliwell and the late Dr Joseph
Mathew, Department of Histopathology, Royal Cornwall Hospitals Trust,
UK.)


Neurones
43
3
RETPAHC
tide subunits, NF-L (68 kDa), NF-M (160 kDa) and NF-H (200 kDa).
NF-M and NF-H have long C-terminal domains that project as side arms
from the assembled neurofilament and bind to neighbouring filaments.
They can be heavily phosphorylated, particularly in the highly stable
neurofilaments of mature axons, and are thought to give axons their
tensile strength. Some axons are almost filled by neurofilaments.
Soma Microtubules are important in axonal transport, although dendrites
Nucleolus usually have more microtubules than axons. Centrioles persist in
Nucleus mature postmitotic neurones, where they are concerned with the gen-
eration of microtubules rather than cell division. Centrioles are associ-
ated with cilia on the surfaces of developing neuroblasts. Their
significance, other than at some sensory endings (e.g. the olfactory
Axon hillock mucosa), is not known.
Pigment granules (Fig. 3.5) appear in certain regions, e.g. neurones
Dendrite of the substantia nigra contain neuromelanin, which is probably a
waste product of catecholamine synthesis. A similar pigment gives a
bluish colour to the neurones in the locus coeruleus. Some neurones
are unusually rich in metals, which may form components of enzyme
Axon systems, e.g. zinc in the hippocampus and iron in the red nucleus.
Ageing neurones, especially in spinal ganglia, accumulate granules of
Myelin sheath lipofuscin (senility pigment) in residual bodies, which are lysosomes
packed with partially degraded lipoprotein material.
DENDRITES
Axodendritic
synapse
Dendrites are highly branched, usually short processes that project from
Axosomatic the soma (see Fig. 3.2; Shah et al 2010). The branching patterns of many
synapse
dendritic arrays are probably established by random adhesive interac-
Axon collateral tions between dendritic growth cones and afferent axons that occur
during development. There is an overproduction of dendrites in early
Axo-axonal
synapse development, and this is pruned in response to functional demand as


the nervous system matures and information is processed through the
dendritic tree. There is evidence that dendritic trees may be plastic
structures throughout adult life, expanding and contracting as the traffic
of synaptic activity varies through afferent axodendritic contacts (for a
Synaptic
review, see Wong and Ghosh (2002)). Groups of neurones with similar
terminals
functions have a similar stereotypic tree structure (Fig. 3.6), suggesting
that the branching patterns of dendrites are important determinants of
the integration of the afferent inputs that converge on the tree. For a
Fig. 3.2 A schematic view of typical neurones featuring one with the review of current research on dendritic trees in the normal and patho-
soma cut away to show the nucleus and cytoplasmic organelles, dendritic logical brain, see Kulkarni and Firestein (2012).
trees with synaptic contacts, other types of synapse, the axon hillock and Dendrites differ from axons in many respects. They represent the
a myelinated axon.
afferent rather than the efferent system of the neurone, and receive both
excitatory and inhibitory axodendritic contacts. They may also make
dendrodendritic and dendrosomatic connections (see Fig. 3.9), some
congregate in large groups associated with the rough endoplasmic retic- of which are reciprocal. Synapses occur either on small projections
ulum. These aggregates of RNA-rich structures are visible by light micro- called dendritic spines or on the smooth dendritic surface. Dendrites
scopy as basophilic Nissl bodies or granules. They are distributed contain ribosomes, smooth endoplasmic reticulum, microtubules, neu-
throughout the cell body and large dendrites; the axon hillock is con- rofilaments, actin filaments and Golgi complexes. Their neurofilament
spicuously ribosome-free. Nissl bodies are more obvious in large, highly proteins are poorly phosphorylated and their microtubules express the
active cells, such as spinal motor neurones (Fig. 3.4), which contain microtubule-associated protein (MAP)-2 almost exclusively in compari-
large stacks of rough endoplasmic reticulum and polyribosome aggre- son with axons.


gates. Maintenance and turnover of cytoplasmic and membranous com- The shapes of dendritic spines range from simple protrusions to
ponents are necessary activities in all cells; the huge total volume of structures with a slender stalk and expanded distal end. Most spines are
cytoplasm within the soma and processes of many neurones requires a not more than 2 µm long, and have one or more terminal expansions;
considerable commitment of protein synthetic machinery. Neurones they can also be short and stubby, branched or bulbous. Large mush-
also synthesize other proteins (enzyme systems, G-protein coupled room spines are assumed to have differentiated in response to afferent
receptors, scaffold proteins) involved in the production of neurotrans- activity (‘memory spines’; Matsuzaki et al 2004). These large spines
mitters and in the reception and transduction of incoming stimuli. often contain a spine apparatus, an organelle consisting of small
Various transmembrane channel proteins and enzymes are located at sacs of endoplasmic reticulum interleaved by electron-dense bars (Gray
the surfaces of neurones, where they are associated with movements 1959, Segal et al 2010). Mouse mutants deficient in these organelles
of ions. show memory deficits (Deller et al 2003). Free ribosomes and polyri-
The nucleus is characteristically large and euchromatic, and contains bosomes are concentrated at the base of the spine. Ribosomal accumu-
at least one prominent nucleolus; these are features typical of all cells lations near synaptic sites provide a mechanism for activity-dependent
engaged in substantial levels of protein synthesis. The cytoplasm con- synaptic plasticity through the local regulation of protein synthesis.
tains many mitochondria and moderate numbers of lysosomes. Golgi
complexes are usually close to the nucleus, near the bases of the main
dendrites and opposite the axon hillock. AXONS
The neuronal cytoskeleton is a prominent feature of its cytoplasm
and gives shape, strength and support to the dendrites and axons. A The axon originates either from the soma or from the proximal segment
number of neurodegenerative diseases are characterized by abnormal of a dendrite at a specialized region free of Nissl granules, the axon


aggregates of cytoskeletal proteins (reviewed in Cairns et al (2004)). hillock (see Fig. 3.2). Action potentials are initiated here, at the junction
Neurofilaments (the intermediate filaments of neurones) and microtu- with the proximal axon (axon initial segment). The axonal plasma
bules are abundant in the soma and along dendrites and axons; the membrane (axolemma) is undercoated at the hillock by a concentration
proportions vary with the type of neurone and cell process. Bundles of of cytoskeletal molecules, including spectrin and actin fibrils, which are
neurofilaments constitute neurofibrils, which can be seen by light important in anchoring numerous voltage-sensitive channels to the
microscopy in silver-stained or immunolabelled sections. Neurofila- membrane. For details, see Bender and Trussell (2012), and for neural
ments are heteropolymers of proteins assembled from three polypep- electrophysiological techniques, see Sakmann and Neher (2009). The


NERvOuS SySTEm
44
1
NOITCES
Sensory Integrative Motor
Dendrites
Apical
dendrites
Sensory endings
e.g. in skin Nissl bodies
in soma
Pyramidal cell
soma
Unipolar
neurone
Purkinje cell
soma
Basal Large motor
dendrites neurone
Axon
Axon
Soma
Peripheral Bipolar
axon neurone
Presynaptic
autonomic
neurone Axon
Soma
Soma
Axon
Soma
Postsynaptic
autonomic
neurone
Axon
Central
axon
Smooth muscle
Axon e.g intestine
Soma
Interneurone Interneurone
Axon
Striated (skeletal)
muscle
Fig. 3.3 The variety of shapes of neurones and their processes. The inset shows a human multipolar retinal ganglion cell, filled with fluorescent dye by
microinjection. (Inset, Courtesy of Drs Richard Wingate, James Morgan and Ian Thompson, King’s College, London.)
Fig. 3.5 Neurones in
the substantia nigra of
the human midbrain,
S showing cytoplasmic
granules of
neuromelanin pigment.
(Courtesy of Mr Peter
Helliwell and the late
Dr Joseph Mathew,
Department of
N Histopathology, Royal
G P Cornwall Hospitals
Trust, UK.)
P
Fig. 3.4 Spinal motor neurones (toluidine blue stained resin section, rat
tissue) showing a group of cell bodies (somata, S), some with the
proximal parts of axonal and dendritic processes (P) visible. Their nuclei
(N) typically have prominent, deeply staining nucleoli, indicative of
metabolically highly active cells; two are visible in the plane of section.
Nissl granules (G) are seen in the cytoplasm. Surrounding the neuronal
somata is the neuropil, consisting of the interwoven processes of these
and other neurones and of glial cells.


Neurones
45
3
RETPAHC
Fig. 3.6 A Purkinje role in Alzheimer’s disease (Cairns et al 2004): formation of tau oli-
neurone from the gomers and the subsequent pathological filament arrays are critical
cerebellum of a rat steps in the aetiopathogenesis of this condition. Neurofilament proteins
stained by the ranging from high to low molecular weights are highly phosphorylated
Golgi–Cox method, in mature axons, whereas growing and regenerating axons express a
showing the extensive calmodulin-binding membrane-associated phosphoprotein, growth-
two-dimensional array associated protein-43 (GAP-43), as well as poorly phosphorylated
of dendrites. (Courtesy
neurofilaments.
of Dr Martin Sadler and
Neurones respond differently to injury, depending on whether the
Professor M Berry,
damage occurs in the CNS or the PNS. The glial microenvironment of
Division of Anatomy
a damaged central axon does not facilitate axonal regrowth; conse-
and Cell Biology, GKT
quently, reconnection with original synaptic targets does not normally
School of Medicine,
occur. In marked contrast, the glial microenvironment in the PNS is
London.)
capable of facilitating axonal regrowth. However, functional outcome
of clinical repair of a large mixed peripheral nerve, especially if the
injury occurs some distance from the target organ, or produces a long
defect in the damaged nerve, is frequently unsatisfactory (Birch 2011;
see also Commentary 1.6).
Axoplasmic flow
Neuronal organelles and cytoplasm are in continual motion. Bidirec-
tional streaming of vesicles along axons results in a net transport of
materials from the soma to the terminals, with more limited movement
in the opposite direction. Two major types of transport occur, one slow
and one relatively fast. Slow axonal transport is a bulk flow of axoplasm
only in the anterograde direction, carrying cytoskeletal proteins and
soluble, non-membrane-bound proteins from the soma to the termi-
axon hillock is unmyelinated and often participates in inhibitory axo-
nals at a rate of approximately 0.1–3 mm a day. In contrast, fast axonal
axonal synapses. It is unique because it contains ribosomal aggregates


transport carries membrane-bound vesicular material (endosomes and
immediately below the postsynaptic membrane (Kole and Stuart 2012).
lysosomal autophagic vacuoles) and mitochondria at approximately
In the CNS, small, unmyelinated axons lie free in the neuropil,
200 mm a day in the retrograde direction (towards the soma) and
whereas in the PNS they are embedded in Schwann cell cytoplasm.
approximately 40 mm per day anterogradely (in particular, synaptic
Myelin, which is formed around almost all axons of >2 µm diameter
vesicles containing neurotransmitters).
by oligodendrocytes in the CNS and by Schwann cells in the PNS,
Rapid flow depends on microtubules. Vesicles with side projections
begins at the distal end of the axon hillock. Nodes of Ranvier are spe-
line up along microtubules and are transported along them by their
cialized regions of myelin-free axon where action potentials are gener-
side arms. Two microtubule-based motor proteins with adenosine 5′-
ated and where an axon may branch. In both CNS and PNS, the territory
triphosphatase (ATPase) activity are involved in fast transport: kinesin
of a myelinated axon between adjacent nodes is called an internode;
family proteins are responsible for the fast component of anterograde
the region close to a node, where the myelin sheath terminates, is called
transport, and cytoplasmic dynein is responsible for retrograde trans-
the paranode; and the region just beyond that is the juxtaparanode.
port. Retrograde transport mediates the movement of neurotrophic
Myelin thickness and internodal lengths are, in general, positively cor-
viruses, e.g. herpes zoster, rabies and polio, from peripheral terminals,
related with axon diameter. The density of sodium channels in the
and their subsequent concentration in the neuronal soma. It has been
axolemma is highest at nodes of Ranvier, and very low along internodal
suggested that specific pools of endocytic organelles, signalling endo-
membranes; sodium channels are spread more evenly within the axo-
somes, mediate the long-distance axonal transport of growth factors,


lemma of unmyelinated axons. Fast potassium channels are present in
such as neurotrophins and their signalling receptors. Defects in axonal
the paranodal regions of myelinated axons. Fine processes of glial cyto-
and dendritic transport have been linked to various neurodegenerative
plasm (astrocytic in the CNS, Schwann cell in the PNS) surround the
processes. See Guzik and Goldstein (2004), Hinckelmann et al (2013)
nodal axolemma.
and Schmieg et al (2014) for reviews of axonal transport in health and
The terminals of an axon are unmyelinated. Most expand into presy-
disease.
naptic boutons, which may form connections with axons, dendrites,
neuronal somata or, in the periphery, muscle fibres, glands and lym-
phoid tissue. Exceptions include the free afferent sensory endings in,
SYNAPSES
for example, the epidermis, which are unspecialized structurally, and
the peripheral terminals of afferent sensory fibres with encapsulated
Transmission of impulses across specialized junctions (synapses)
endings (see Fig. 3.27). Axon terminals contain abundant small clear
between two neurones is largely chemical and depends on the release
synaptic vesicles and large dense-core vesicles. The former contain a
of neurotransmitters from the presynaptic terminal. These neurotrans-
neurotransmitter (e.g. glutamate, γ-aminobutyric acid (GABA), acetyl-
mitters bind to cognate receptors in the postsynaptic neuronal mem-
choline) that is released into the synaptic cleft on the arrival of an action
brane, resulting in a change of membrane conductance and leading to
potential at the terminal and which then binds to cognate receptors on
either a depolarization or a hyperpolarization (Ryan and Grant 2009).
the postsynaptic membrane. Depending on the nature of the transmit-
The patterns of axonal termination vary considerably. A single axon
ter and its receptors, the postsynaptic neurone will become excited or
may synapse with one neurone (e.g. climbing fibres ending on cere-
inhibited. The dense-core vesicles contain neuropeptides, including
bellar Purkinje neurones), or more often with many neurones (e.g.


brain-derived neurotrophic factor (BDNF; Dieni et al 2012). Axon ter-
cerebellar parallel fibres, which provide an extreme example of this
minals may themselves be contacted by other axons, forming axo-
phenomenon). In synaptic glomeruli (e.g. in the olfactory bulb), groups
axonal presynaptic inhibitory circuits. Further details of neuronal
of synapses between two or many neurones form interactive units
microcircuitry are given in Kandel et al (2012) and Haines (2006).
encapsulated by neuroglia (Fig. 3.7; Perea et al 2009).
Axons contain microtubules, neurofilaments, mitochondria, mem-
Electrical synapses (direct communication via gap junctions) are rare
brane vesicles, cisternae and lysosomes. They do not usually contain
in the human CNS and are confined largely to groups of neurones with
ribosomes or Golgi complexes, other than at the axon hillock; excep-
tightly coupled activity, e.g. the inspiratory centre in the medulla. They
tionally, the neurosecretory fibres of hypothalamo-hypophysial neu-
will not be discussed further here.
rones contain the mRNA of neuropeptides. Organelles are differentially
distributed along axons, e.g. there is a greater density of mitochondria
Classification of chemical synapses
and membrane vesicles in the axon hillock, at nodes and in presynaptic
endings. Axonal microtubules are interconnected by cross-linking
MAPs, of which tau is the most abundant. Microtubules have an intrin- Chemical synapses have an asymmetric structural organization (Figs
sic polarity, and in axons all microtubules are uniformly orientated with 3.8–3.9) in keeping with the unidirectional nature of their transmis-
their rapidly growing ends directed away from the soma towards the sion. Typical chemical synapses share a number of important features.
axon terminal. The microtubule binding protein tau plays an important They all display an area containing a presynaptic density apposed to a


NERvOuS SySTEm
46
1
NOITCES
Axon of Golgi cell Soma of granule cell corresponding postsynaptic density; the two are separated by a narrow
(20–30 nm) gap, the synaptic cleft. Synaptic vesicles containing the
appropriate neurotransmitter are found on the presynaptic side, clus-
tered near the presynaptic density at the presynaptic membrane.
Together these define the active zone, the area of the synapse where
neurotransmission takes place (Eggermann et al 2012, Gray 1959).
Chemical synapses can be classified according to a number of dif-
ferent parameters, including the neuronal regions forming the synapse,
their ultrastructural characteristics, the chemical nature of their
neurotransmitter(s) and their effects on the electrical state of the post-
synaptic neurone. The following classification is limited to associations
– between neurones. Neuromuscular junctions share many (though not
– all) of these parameters, and are often referred to as peripheral synapses.
+
They are described separately on page 63.
+ Synapses can occur between almost any surface regions of the par-
ticipating neurones. The most common type occurs between an axon
and either a dendrite or a soma, when the axon is expanded as a small
bulb or bouton (see Figs 3.8–3.9). This may be a terminal of an axonal
branch (terminal bouton) or one of a row of bead-like endings, when
the axon makes contact at several points, often with more than one
+ neurone (bouton de passage). Boutons may synapse with dendrites,
–
including thorny protrusions named dendritic spines or the flat surface
+
of a dendritic shaft; a soma (usually on its flat surface, but occasionally
on spines); the axon hillock; and the terminal boutons of other axons.
The connection is classified according to the direction of transmis-
sion, and the incoming terminal region is named first. Most common
are axodendritic synapses, although axosomatic connections are fre-
quent. All other possible combinations are found but are less common,
i.e. axo-axonal, dendro-axonal, dendrodendritic, somatodendritic or


somatosomatic. Axodendritic and axosomatic synapses occur in all
regions of the CNS and in autonomic ganglia, including those of
the ENS. The other types appear restricted to regions of complex inter-
action between larger sensory neurones and microneurones, e.g. in the
thalamus.
Neuroglial cell Mossy fibre Dendrite of Ultrastructurally, synaptic vesicles may be internally clear or dense,
axon terminal Golgi cell
and of different size (loosely categorized as small or large) and shape
Fig. 3.7 The arrangement of a complex synaptic unit. A cerebellar (round, flat or pleomorphic, i.e. irregularly shaped). The submembra-
synaptic glomerulus with excitatory (‘+’) and inhibitory (‘−’) synapses nous densities may be thicker on the postsynaptic than on the presyn-
grouped around a central axonal bouton. The directions of transmission aptic side (asymmetric synapses), or equivalent in thickness (symmetrical
are shown by the arrows. synapses), and can be perforated or non-perforated. Synaptic ribbons
Fig. 3.8 Electron micrographs demonstrating
various types of synapse. A, A cross-section of a
dendrite (D) on which two synaptic boutons (B)
end. The upper bouton contains round vesicles,
and the lower bouton contains flattened vesicles
of the small type. A number of pre- and
BB
postsynaptic (P) thickenings mark the specialized
zones of contact. B, A type I synapse
P BB (S, postsynaptic site) containing both small, round,
clear vesicles and also large, dense-cored vesicles
** of the neurosecretory type. C, A large terminal
bouton (B) of an optic nerve afferent fibre, which
DD is making contact with a number of postsynaptic
processes, in the dorsal lateral geniculate nucleus
BBff
of the rat. One of the postsynaptic processes (*)
also receives a synaptic contact from a bouton
PP
PP (Bf) containing flattened vesicles. D, Reciprocal
synapses (S) between two neuronal processes in
the olfactory bulb. (Courtesy of Professor AR
BB
Lieberman, Department of Anatomy, University
College, London.)
C
A


SS
SS
SS
B D


Neurones
47
3
RETPAHC
A Excitatory synapses Serial synapses B Axosomatic
synapses
Bouton With small With dense Excitatory Inhibitory
de passage clear spherical catecholamine- to dendrite axo-axonal
vesicles containing vesicles synapse
Capillary
Dendrite
Nucleus
C Ribbon synapse
Axo-initial segment
Retinal synapse
rod
With small With large Inhibitory to dendrite
flattened flattened Excitatory in opposite
vesicles vesicles direction
Neurosecretory
Inhibitory synapses Reciprocal synapse ending
Fig. 3.9 The structural arrangements of different types of synaptic contact.
are found at sites of neurotransmission in the retina and inner ear. They instances, types I and II synapses are found in close proximity, orien-
have a distinctive morphology, in that the synaptic vesicles are grouped tated in opposite directions across the synaptic cleft (a reciprocal
around a ribbon- or rod-like density orientated perpendicular to the synapse).
cell membrane (see Fig. 3.9).
Mechanisms of synaptic activity
Synaptic boutons make obvious close contacts with postsynaptic
structures but many other terminals lack specialized contact zones. Synaptic activation begins with arrival of one or more action potentials
Areas of transmitter release occur in the varicosities of unmyelinated at the presynaptic bouton, which causes the opening of voltage-sensitive
axons, where effects are sometimes diffuse, e.g. the aminergic pathways calcium channels in the presynaptic membrane. The response time in
of the basal ganglia, and in autonomic fibres in the periphery. In some typical fast-acting synapses is then very rapid; classic neurotransmitter
instances, such axons may ramify widely throughout extensive areas of (e.g. ACh, glutamate or GABA) is released in less than a millisecond.
the brain and affect the behaviour of very large populations of neu- Release-ready synaptic vesicles are docked to the presynaptic membrane
rones, e.g. the diffuse cholinergic innervation of the cerebral cortices. and primed through processes not yet fully understood. On Ca2+ influx
Pathological degeneration of these pathways can therefore cause wide- through voltage-sensitive channels, their membranes fuse to open a


spread disturbances in neural function. pore through which neurotransmitter diffuses into the synaptic cleft
Neurones express a variety of neurotransmitters, either as one class (Eggermann et al 2012; Gray 1959).
of neurotransmitter per cell or more often as several. Good correlations Once the vesicle has discharged its contents, its membrane is incor-
exist between some types of transmitter and specialized structural porated into the presynaptic plasma membrane and is then recycled
features of synapses. In general, asymmetric synapses with relatively back into the bouton by endocytosis near the edges of the active zone.
small spherical vesicles are associated with acetylcholine (ACh), gluta- The recycling time for a synaptic vesicle may be in the range of a few
mate, serotonin (5-hydroxytryptamine, 5-HT) and some amines; those seconds to minutes; newly recycled vesicles may be used instantly for
with dense-core vesicles include many peptidergic synapses and the next cycle of neurotransmitter release (cycling pool of vesicles). The
other amines (e.g. noradrenaline (norepinephrine), adrenaline (epine- fusion of vesicles with the presynaptic membrane is responsible for the
phrine), dopamine). Symmetrical synapses with flattened or pleomor- observed quantal behaviour of neurotransmitter release, both during
phic vesicles have been shown to contain either GABA or glycine. neural activation and spontaneously, in the slightly leaky resting condi-
Neurosecretory endings found in various parts of the brain and in tion (Neher and Sakaba 2008; Suedhof 2012).
neuroendocrine glands and cells of the dispersed neuroendocrine Postsynaptic events vary greatly, depending on the receptor mole-
system share many features with presynaptic boutons. They all contain cules and their related molecular complexes (Murakoshi and Yasuda
peptides or glycoproteins within dense-core vesicles. The latter are of 2012). Receptors are generally classed as either ionotropic or metabo-
characteristic size and appearance: they are often ellipsoidal or irregular tropic. Ionotropic receptors are multimeric protein complexes that
in shape, and relatively large, e.g. oxytocin and vasopressin vesicles in harbour intrinsic ion channels that can be operated by conformational


the neurohypophysis may be up to 200 nm in diameter. changes induced when neurotransmitter molecules bind the receptor
Synapses may cause depolarization or hyperpolarization of the post- complex, causing a voltage change within the postsynaptic cell. Exam-
synaptic membrane, depending on the neurotransmitter released and ples are the nicotinic ACh receptor and the related GABA A receptor,
the classes of receptor molecule in the postsynaptic membrane. Depo- which are formed from five subunits, and the tetrameric ionotropic
larization of the postsynaptic membrane results in excitation of the glutamate receptors, such as the N-methyl-D-aspartate (NMDA)
postsynaptic neurone, whereas hyperpolarization has the effect of tran- receptor or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
siently inhibiting electrical activity. Subtle variations in these responses (AMPA) receptor. Alternatively, the receptor and ion channel may be
may also occur at synapses where mixtures of neuromediators are separate molecules, coupled by G-proteins, some via a complex cascade
present and their effects are integrated. For details of the synaptic organ- of chemical interactions (a second messenger system), e.g. the adenylate
ization of the brain, see Shepherd (2003). cyclase pathway. Postsynaptic effects are generally rapid and short-lived,
because the transmitter is quickly inactivated either by an extracellular
Type I and II synapses
enzyme (e.g. acetylcholinesterase, AChE), or by uptake into neurones
There are two broad categories of synapse, type I and type II. In active or glial cells. Examples of such metabotropic receptors are the mus-
zones of type I synapses the cytoplasmic density is thicker on the post- carinic ACh receptor and the dopamine receptor.
synaptic side. In type II synapses the pre- and postsynaptic densities are
thinner and more symmetrical. Type I boutons contain a predominance Neurohormones
of small spherical vesicles approximately 50 nm in diameter, and type Neurohormones are included in the class of molecules with
II boutons contain oval or flattened vesicles. Throughout the CNS, type neurotransmitter-like activity. They are synthesized in neurones and


I synapses are generally excitatory and type II are inhibitory. In a few released into the blood circulation by exocytosis at synaptic bouton-like


NERvOuS SySTEm
48
1
NOITCES
structures. As with classic endocrine gland hormones, they may act at lie mainly in the brainstem, although their axons ramify widely into all
great distances from their site of secretion. Neurones secrete into the parts of the nervous system. Monoaminergic cells are also present in
CSF or local interstitial fluid to affect other cells, either diffusely or at the retina.
a distance. To encompass this wide range of phenomena the general Noradrenaline is the chief transmitter present in sympathetic gangli-
term neuromediation has been used, and the chemicals involved are onic neurones with endings in various tissues, notably smooth muscle
called neuromediators. and glands, and in other sites including adipose and haemopoietic
tissues and the corneal epithelium. It is also found at widely distributed
Neuromodulators synaptic endings within the CNS, many of them the terminals of neu-
Some neuromediators do not appear to affect the postsynaptic mem- ronal somata situated in the locus coeruleus in the medullary floor. The
brane directly but they can affect its responses to other neuromediators, actions of noradrenaline depend on its site of action and vary with the
either enhancing their activity (by increasing or prolonging the immedi- type of postsynaptic receptor, e.g. it strongly inhibits neurones of
ate response), or perhaps limiting or inhibiting their action. These the submucosal plexus of the intestine and of the locus coeruleus via
substances are called neuromodulators. A single synaptic terminal may α 2-adrenergic receptors, whereas it mediates depolarization, producing
contain one or more neuromodulators in addition to a neurotransmit- vasoconstriction, via β-receptors in vascular smooth muscle. Adrenaline
ter, usually (though not always) in separate vesicles. Neuropeptides (see is present in central and peripheral nervous pathways and occurs
below) are nearly all neuromodulators, at least in some of their actions. with noradrenaline in the suprarenal medulla. Both adrenaline and
They are stored within dense granular synaptic vesicles of various sizes noradrenaline are found in dense-cored synaptic vesicles approximately
and appearances. 50 nm in diameter.


Dopamine is a neuromediator of considerable clinical importance,
Development and plasticity of synapses found mainly in neurones with cell bodies in the telencephalon,
diencephalon and mesencephalon. A major dopaminergic neuronal
population in the midbrain constitutes the substantia nigra, so called
Embryonic synapses first appear as inconspicuous dense zones flanking
because its cells contain neuromelanin, a black granular by-product
synaptic clefts. Immature synapses often appear after birth, suggesting
of dopamine synthesis. Dopaminergic endings are particularly numer-
that they may be labile, and are reinforced if transmission is function-
ous in the corpus striatum, limbic system and cerebral cortex. Structur-
ally effective, or withdrawn if redundant. This is implicit in some theo-
ally, dopaminergic synapses contain numerous dense-cored vesicles
ries of memory (Squire and Kandel 2008), which postulate that synapses
that resemble those containing noradrenaline. Pathological reduction
are modifiable by frequency of use, to establish preferential conduction
in dopaminergic activity has widespread effects on motor control,
pathways. Evidence from hippocampal neurones suggests that even
affective behaviour and other neural activities, as seen in Parkinson’s
brief synaptic activity can increase the strength and sensitivity of the
syndrome.
synapse for some hours or longer (long-term potentiation, LTP). During
Serotonin and histamine are found in neurones mainly within the
early postnatal life, the normal developmental increase in numbers and
CNS. Serotonin is typically synthesized in small midline neuronal clus-
sizes of synapses and dendritic spines depends on the degree of neural
ters in the brainstem, mainly in the raphe nuclei; the axons from these
activity and is impaired in areas of damage or functional deprivation.
neurones ramify extensively throughout the entire brain and spinal
cord. Synaptic terminals contain rounded, clear vesicles approximately
Neurotransmitter molecules 50 nm in diameter and are of the asymmetrical type. Histaminergic
neurones appear to be relatively sparse and are restricted largely to the
Until recently, the molecules known to be involved in chemical syn- hypothalamus.
apses were limited to a fairly small group of classic neurotransmitters,
Amino acids


e.g. ACh, noradrenaline (norepinephrine), adrenaline (epinephrine),
dopamine and histamine, all of which had well-defined rapid effects There are three major amino acids: GABA, glutamate and glycine, which
on other neurones, muscle cells or glands. However, many synaptic bind to specific receptors (Barrera and Edwardson 2008). GABA is a
interactions cannot be explained on the basis of classic neurotransmit- major inhibitory transmitter released at the terminals of local circuit
ters, and it is now known that other substances, particularly some neurones within the brainstem and spinal cord (e.g. the recurrent inhib-
amino acids such as glutamate, glycine, aspartate, GABA and the itory Renshaw loop), cerebellum (where it is the main transmitter of
monoamine, serotonin, also function as transmitters. Substances first Purkinje cells), basal ganglia, cerebral cortex, thalamus and subthala-
identified as hypophysial hormones or as part of the dispersed neuroen- mus. It is stored in flattened or pleomorphic vesicles within symmetrical
docrine system (see below) of the alimentary tract, can be detected synapses. GABA may be inhibitory to postsynaptic neurones, or may
widely throughout the CNS and PNS, often associated with functionally mediate either presynaptic inhibition or facilitation, depending on the
integrated systems. Many of these are peptides; more than one hundred synaptic arrangement (Gassmann and Bettler 2012).
(together with other candidates) function mainly as neuromodulators Glutamate is the major excitatory transmitter present widely within
and influence the activities of classic transmitters. the CNS, including the major projection pathways from the cortex to
the thalamus, tectum, substantia nigra and pontine nuclei. It is found
Acetylcholine in the central terminals of the auditory and trigeminal nerves, and in
Acetylcholine (ACh) is perhaps the most extensively studied neuro- the terminals of parallel fibres ending on Purkinje cells in the cerebel-
transmitter of the classic type. Its precursor, choline, is synthesized in lum. Structurally, glutamate is associated with asymmetrical synapses


the neuronal soma and transported to the axon terminals, where it is containing small (approximately 30 nm), round, clear synaptic vesicles
acetylated by the enzyme choline acetyl transferase (ChAT), and stored (Contractor et al 2011). For further reading, see Willard and Koochek-
in clear spherical vesicles 40–50 nm in diameter. ACh is synthesized by pour (2013).
motor neurones and released at all their motor terminals on skeletal Glycine is a well-established inhibitory transmitter of the CNS, par-
muscle. It is released by preganglionic fibres at synapses in parasympa- ticularly the lower brainstem and spinal cord, where it is mainly found
thetic and sympathetic ganglia, and many parasympathetic, and some in local circuit neurones. Recent evidence suggests that glycine may also
sympathetic, ganglionic neurones are cholinergic. ACh is also associ- be released from glutamatergic axon terminals to participate in activa-
ated with the degradative extracellular enzyme AChE, which inactivates tion of NMDA receptors, and from astrocytes into the synaptic cleft via
the transmitter by converting it to choline. activation of non-NMDA-type glutamatergic ionotropic receptors in
The effects of ACh on nicotinic receptors (i.e. those in which nicotine the glial cell membrane (see Harsing and Matyus (2013) for further
is an agonist) are rapid and excitatory. In the CNS, the nicotinic ACh references).
receptor mediates the effect of tobacco (for review, see Albuquerque
ATP and adenosine
et al (2009)). In the peripheral autonomic nervous system, the slower,
more sustained excitatory effects of cholinergic autonomic endings are ATP serves not only as a universal energy substrate, but also as an extra-
mediated by muscarinic receptors via a second messenger system. cellular signalling molecule. Specific ionotropic (P2X) and metabo-
tropic (P2Y) receptors are expressed in neurones and even more
Monoamines
prominently on all types of glial cell. Adenosine is a degradation
Monoamines include the catecholamines (noradrenaline (norepine- product of ATP and has specific metabotropic receptors that may be


phrine), adrenaline (epinephrine) and dopamine), the indoleamine located presynaptically (Burnstock et al 2011).
serotonin (5-hydroxytryptamine, 5-HT) and histamine (Haas et al
Nitric oxide
2008). They are synthesized by neurones in sympathetic ganglia and by
their homologues, the chromaffin cells of the suprarenal medulla and Nitric oxide (NO) is of considerable importance at autonomic and
paraganglia. Within the CNS, the somata of monoaminergic neurones enteric synapses, where it mediates smooth muscle relaxation. It


Central glia
49
3
RETPAHC
functions in several types of synaptic plasticity, including hippocampal Subpial end-foot Neurone Tanycyte
long-term potentiation (LTP), when it may act as a retrograde messen- Perineuronal
Pia mater Astrocyte end-foot Microglial cell Ependymal cellVentricle
ger after postsynaptic NMDA receptor activation. NO is able to diffuse
freely through cell membranes, and so is not under such tight quantal
control as vesicle-mediated neurotransmission.
Neuropeptides
Many neuropeptides coexist with other neuromediators in the same
synaptic terminals. As many as three peptides often share a particular
ending with a well-established neurotransmitter, in some cases within
the same synaptic vesicles. Some peptides occur in both the CNS and
the PNS, particularly in the ganglion cells and peripheral terminals
of the ANS, whilst others are entirely restricted to the CNS. Only a
few examples are given here.
Most of the neuropeptides are classified according to the site where
they were first discovered. For example, the gastrointestinal peptides
were initially found in the gut wall, and a group that includes releasing
hormones, adenohypophysial and neurohypophysial hormones was Myelinated Oligodendrocyte Capillary Pericapillary Astrocyte
axon end-foot
first associated with the pituitary gland. Some of these peptides are
Fig. 3.10 The different types of non-neuronal cell in the CNS and their
closely related to each other in their chemistry because they are derived
structural organization and interrelationships with each other and with
from the same gene products (e.g. the pro-opiomelanocortin group),
neurones.
which are cleaved to produce smaller peptides.
Substance P (SP) was the first of the peptides to be characterized as
a gastrointestinal neuromediator and is considered to be the proto-
typic neuropeptide. It is an 11-amino-acid polypeptide that belongs to
ASTROCYTES
the tachykinin neuropeptide family, and is a major neuromediator in
the brain and spinal cord. Contained within large granular synaptic
Astrocytes are the most abundant and diverse glial cell type but their


vesicles, SP is found in approximately 20% of dorsal root and trigemi-
identity is not well defined (Matyash and Kettenmann 2010). There is
nal ganglion cells, in particular in small nociceptive neurones, and in
no common marker that labels all astrocytes, in the way that myelin
some fibres of the facial, glossopharyngeal and vagal nerves. Within
basic protein is a marker for oligodendrocytes or the calcium-binding
the CNS, SP is present in several apparently unrelated major pathways,
protein Iba1 is a marker for microglia. A commonly used marker is the
and has been described in the limbic system, basal ganglia, amygdala
expression of glial fibrillary acidic protein (GFAP), which forms inter-
and hypothalamus. Its known action is prolonged postsynaptic
mediate filaments, but GFAP is not expressed in all astrocytes.
excitation, particularly from nociceptive afferent terminals, which sus-
The morphology of astrocytes is extremely diverse. Classically, two
tains the effects of noxious stimuli. SP is one of the main neuropep-
forms were distinguished: protoplasmic and fibrous astrocytes. Proto-
tides that trigger an inflammatory response in the skin and has
plasmic astrocytes (star-shaped cells) are found in grey matter, possess
also been implicated in the vomiting reflex, changes in cardiovascular
several stem processes that branch further into a very complex network,
tone, stimulation of salivary secretion, smooth muscle contraction,
and contact synapses, both at the pre- and postsynaptic membranes.
and vasodilation.
Fibrous astrocytes are predominantly found in white matter and their
Vasoactive intestinal polypeptide (VIP), another gastrointestinal
processes are often orientated in parallel with the axons. Radial glial
peptide, is widely present in the CNS, where it is probably an excitatory
cells are found early in development and serve as stem cells for neu-
neurotransmitter or neuromodulator. It is found in distinctive bipolar
rones and glial cells. They may be categorized as astrocytes because they
neurones of the cerebral cortex; small dorsal root ganglion cells, par-
transform later in development into typical astrocytes. There are a


ticularly of the sacral region; the median eminence of the hypothala-
number of other types of astrocyte with specialized morphologies. Berg-
mus, where it may be involved in endocrine regulation; intramural
mann glial cells in the cerebellum have somata in the Purkinje cell layer,
ganglion cells of the gut wall; and sympathetic ganglia.
processes that intermingle with the dendritic trees of the Purkinje
Somatostatin (ST, somatotropin release inhibiting factor) has a
neurones and terminal end-feet at the pial surface. Müller cells in the
broad distribution within the CNS, and may be a central neurotransmit-
retina have a radial morphology and span the entire retina. Other
ter or neuromodulator. It also occurs in small dorsal root ganglion cells.
astrocytic cells are tanycytes, velate astrocytes (cerebellum) and pitui-
Beta-endorphin, leu- and metenkephalins, and the dynorphins belong
cytes (infundibulum and neurohypophysis of the pituitary gland).
to a group of peptides called the naturally occurring opiates that possess
Pituicyte processes end mostly on endothelial cells in the neurohypo-
analgesic properties. They bind to opiate receptors in the brain where,
physis and tuber cinereum.
in general, their action seems to be inhibitory. Enkephalins have been
Astrocyte complexity and morphological diversity has reached the
localized in many areas of the brain. Their particular localization in the
highest evolutionary level in humans (Fig. 3.11). A single astrocyte may
septal nuclei, amygdaloid complex, basal ganglia and hypothalamus
enwrap several neuronal somata and make contacts with tens of thou-
suggests that they are important mediators in the limbic system and in
sands of individual synapses; bipolar astrocytes located in layer 5 and
the control of endocrine function. They have also been implicated
6 of the cortex may extend processes up to 1 mm long.
strongly in the central control of pain pathways, because they are found
Astrocytes in grey matter form a syncytium in which cells are inter-
in the peri-aqueductal grey matter of the midbrain, a number of reticu-


connected by gap junctions, permitting the exchange of ions (e.g.
lar raphe nuclei, the spinal nucleus of the trigeminal nerve and the
calcium, propagated in waves) and small molecules such as ATP or
substantia gelatinosa of the spinal cord. The enkephalinergic pathways
glucose. They are the only cells in the brain capable of converting
exert an important presynaptic inhibitory action on nociceptive affer-
glucose into glycogen, which serves as an energy store. Before re-releasing
ents in the spinal cord and brainstem. Like many other neuromediators,
glucose, astrocytes convert it to lactate, which is taken up by neurones;
enkephalins also occur widely in other parts of the brain in lower
failure in glucose flow through the astrocytic network results in impair-
concentrations.
ment of neuronal function.
Astrocytes not only respond to neuronal activity but also modulate
that activity. They enwrap all penetrating and intracerebral arterioles
CENTRAL GLIA
and capillaries, control the ionic and metabolic environment of the
neuropil and mediate neurovascular coupling. They form specialized
Glial (neuroglial) cells (Fig 3.10) vary considerably in type and number structures that contact either the pial surface (as the glia limitans) or
in different regions of the CNS. There are two major groups, macroglia blood vessels; their end-feet entirely enwrap blood vessels and are
(astrocytes and oligodendrocytes) and microglia, classified according to instrumental in the induction of the blood–brain barrier.
origin. Macroglia arise within the neural plate, in parallel with neu- Traumatic injury to the CNS induces astrogliosis, seen as a local
rones, and constitute the great majority of glial cells. Their functions increase in the number and size of GFAP-positive cells and a character-
are diverse and are now known to extend beyond a passive supporting istic extensive meshwork of processes. The microenvironment of this
role (reviewed in Kettenmann and Ransom (2012)). Microglia have a glial scar, which may also include cells of oligodendrocyte lineage and


small soma (see Fig. 3.19) and are derived from a distinct lineage of myelin debris, plays an important role in inhibiting regrowth of
monocytic cells originating from the yolk sac. damaged CNS axons (Robel et al 2011, Seifert et al 2006).


Nervous system
49.e1
3
RETPAHC
Astrocytes control the diameter of the vessels they contact and can
trigger either their dilation or their contraction, depending on the sub-
stances they release and the levels of associated neuronal activity. They
express water channels (aquaporins) at the end-feet covering the capil-
laries; it has been suggested that this may represent the means by which
astrocytes control brain volume (Tait et al 2008), and it may be relevant
to understanding mechanisms of brain tissue swelling, a major clinical
complication. Astrocytes express different glutamate transporters that
efficiently maintain low levels of extracellular glutamate, which is
excitotoxic. Internalized glutamate is converted into glutamine and
released from astrocytes to be taken up by local neurones and recon-
verted to glutamate via the glutamate–glutamine cycle. They play a
similar role in controlling extracellular GABA levels via expression of
GABA transporters. Astrocytes possess both passive and active mecha-
nisms to control extracellular potassium levels at a resting level of about
3 mmol. They also express transporters that regulate pH and are thought
to play an important role in controlling extracellular pH in the brain.
For further reading on the concept of the ‘tripartite synapse’, where
astrocytic processes interact with pre- and postsynaptic neuronal ele-
ments, see Haydon and Carmignoto (2006).
It has become evident that astrocytes are involved in the modulation
of long-term potentiation (considered as a cellular mechanism of
memory formation) and heterosynaptic depression. They modulate
neuronal activity by releasing neuroactive substances such as D-serine,
ATP or glutamate; it is unclear whether they express all the elements
required for neurotransmitter release by a vesicular mechanism (Parpura
and Zorec 2010).


NERvOuS SySTEm
50
1
NOITCES
Fig. 3.11 Human protoplasmic astrocytes are
larger and more complicated than their rodent
counterparts. A, A typical mouse protoplasmic
astrocyte. Glial fibrillary acidic protein (GFAP)
immunostain; white. SB = 20 µm. B, A typical
human protoplasmic astrocyte to the same scale.
SB = 20 µm. (From Oberheim NA, Takano T, Han
X, et al 2009 Uniquely hominid features of adult
human astrocytes. J Neurosci 29:3276–87.)
A B
A which means that a free exchange of molecules occurs between blood
and adjacent brain. Most of these areas are situated close to the ventri-
cles and are known as circumventricular organs; these areas make up
Astrocyte end-foot
less than 1% of the total area of the brain. Elsewhere, unrestricted
Basal lamina diffusion through the blood–brain barrier is only possible for sub-
stances that can cross biological membranes because of their lipophilic
Pia mater character. Lipophilic molecules may be actively re-exported by the
(larger vessels only) brain endothelium.
Breakdown of the blood–brain barrier occurs when the brain is
Pericyte under damaged by ischaemia or infection, and is also associated with primary
the basal lamina and metastatic cerebral tumours. Reduced blood flow to a region of the
brain alters the permeability and regulatory transport functions of the
barrier locally; the increased stress on compromised endothelial cells
results in leakage of fluid, ions, serum proteins and intracellular sub-
stances into the extracellular space of the brain. The integrity of the
barrier can be evaluated clinically using computed tomography and
B functional magnetic resonance imaging. Breakdown of the blood–brain
barrier may be seen at postmortem in jaundiced patients who have had
Pericyte Astrocyte an infarction. Normally, the brain, spinal cord and peripheral nerves
end-foot remain unstained by the bile post mortem, although the choroid plexus
Perivascular cell is often stained a deep yellow. However, areas of recent infarction (1–3
(macrophage) days) will also be stained by bile pigment because of the localized


breakdown of the blood–brain barrier.
OLIGODENDROCYTES
Endothelium
Oligodendrocytes myelinate CNS axons and are most commonly seen
as intrafascicular cells in myelinated tracts (Figs 3.13–3.14). They
Basal lamina usually have round nuclei and their cytoplasm contains numerous
mitochondria, microtubules and glycogen. They display a spectrum of
Fig. 3.12 The relationship between the glia limitans, perivascular cells morphological variation, from cells with large euchromatic nuclei and
and blood vessels within the brain, in longitudinal (A) and transverse pale cytoplasm, to cells with heterochromatic nuclei and dense cyto-
(B) sections. A sheath of astrocytic end-feet wraps around the vessel and, plasm. In contrast to Schwann cells, which myelinate only one axonal
in vessels larger than capillaries, its investment of pial meninges. Vascular segment, individual oligodendrocytes myelinate up to 50 axonal seg-
endothelial cells are joined by tight junctions and supported by pericytes; ments. Some oligodendrocytes are not associated with axons, and are
perivascular macrophages lie outside the endothelial basal lamina (light either precursor cells or perineuronal (satellite) oligodendrocytes with
blue). processes that ramify around neuronal somata.
Within tracts, interfascicular oligodendrocytes are arranged in long
rows interspersed at regular intervals with single astrocytes. Since oli-
Blood–brain barrier
godendrocyte processes are radially aligned to the axis of each row,
myelinated tracts typically consist of cables of axons myelinated by a
Proteins circulating in the blood enter most tissues of the body except row of oligodendrocytes running down the axis of each cable.
those of the brain, spinal cord and peripheral nerves. This concept of a Oligodendrocytes originate from the ventricular neurectoderm and
blood–brain or a blood–nerve barrier applies to many substances – the subependymal layer in the fetus, and continue to be generated from
some are actively transported across the blood–brain barrier, others are the subependymal plate postnatally. Stem cells migrate and seed into


actively excluded. The blood–brain barrier is located at the capillary white and grey matter to form a pool of adult progenitor cells, which
endothelium within the brain and is dependent on the presence of tight can later differentiate to replenish defunct oligodendrocytes, and pos-
junctions (occluding junctions, zonulae adherentes) between endothe- sibly remyelinate axons in pathologically demyelinated regions. These
lial cells coupled with a relative lack of transcytotic vesicular transport. cells display a highly branching morphology and express a specific
The tightness of the barrier is substantially supported by the close chondroitin sulphate proteoglycan (Neuron Glia 2 (NG2) in rats and
apposition of astrocytes, which direct the formation of endothelial tight its homologue, melanoma cell surface chondroitin sulphate proteo-
junctions, to blood capillaries (reviewed in Abbott et al (2006), Cardoso glycan (MSCP), in humans). The name NG2 cell is used to describe the
et al (2010); Fig. 3.12). cells in both species: several different names have also been used since
The blood–brain barrier develops during embryonic life but may it was first recognized, including polydendrocyte (Nishiyama et al
not be fully completed by birth. There are certain areas of the adult 2009) and syantocyte (Butt et al 2005). NG2 cells express a complex
brain where the endothelial cells are not linked by tight junctions, set of voltage-gated channels and ionotropic receptors for glutamate


Central glia
51
3
RETPAHC
Oligodendrocyte Lateral loop
Node of Ranvier Nucleus Outer loop
A
N
Fig. 3.15 A node of Ranvier (N) in the central nervous system of a rat.
The pale-staining axon (A) is ensheathed by oligodendrocyte myelin
(arrow), apart from a short, exposed region at the node. Toluidine blue
stained resin section. (Courtesy of Dr Clare Farmer, King’s College,
London.)
and GABA; they form direct synapses with axons, enabling transient
activation of these receptors (Hill and Nishiyama 2014). There is con-
siderable support for the view that the NG2 cell is a distinct glial type.
Nodes of Ranvier and incisures of
Schmidt–Lanterman
The territory ensheathed by an oligodendrocyte (or Schwann cell)
process defines an internode, the interval between internodes is called
a node of Ranvier (Fig. 3.15) and the territory immediately adjacent to
the nodal gap is a paranode, where loops of oligodendrocyte cytoplasm
Axon Longitudinal Inner loop Myelin sheath abut the axolemma. Nodal axolemma is contacted by fine filopodia of
incisures perinodal cells, which have been shown in animal studies to have a
Fig. 3.13 The ensheathment of a number of axons by the processes of presumptive adult oligodendrocyte progenitor phenotype; their func-
an oligodendrocyte. The oligodendrocyte soma is shown in the centre tion is unknown. Schmidt–Lanterman incisures are helical decompac-
and its myelin sheaths are unfolded to varying degrees to show their tions of internodal myelin where the major dense line of the myelin
extensive surface area. (Modified from Morell P, Norton WT (1980, May). sheath splits to enclose a spiral of oligodendrocyte cytoplasm. Their
Myelin, Scientific American, 242(5), 88–90, 92, 96 and Raine CS (1984),
structure suggests that they may play a role in the transport of molecules


Morphology of Myelin and Myelination. In Myelin, 2nd ed. P Morell (ed)
across the myelin sheath, but their function is not known.
New York (Plenum Press), by permission.)
MYELIN AND MYELINATION
Myelin is formed by oligodendrocytes (CNS) and Schwann cells (PNS).
A single oligodendrocyte may ensheathe up to 50 separate axon seg-
ments, depending on calibre, whereas myelinating Schwann cells
ensheathe axons on a 1 : 1 basis.
In general, myelin is laid down around axons above 2 µm in diam-
eter. However, the critical minimal axon diameter for myelination is
smaller and more variable in the CNS than in the PNS (approximately
0.2 µm in the CNS compared with 1–2 µm in the PNS). There is con-
siderable overlap between the size of the smallest myelinated and the
largest unmyelinated axons, and so axonal calibre is unlikely to be the
only factor in determining myelination. Moreover, the first axons to
become ensheathed ultimately attain larger diameters than those that
are ensheathed at a later date. There is a reasonable linear relationship
between axon diameter and internodal length and myelin sheath thick-
ness: as the sheath thickens from a few lamellae to up to 200, the axon
may also grow from 1 to 15 µm in diameter. Internodal lengths increase
A about 10-fold during the same time (Nave 2010).
It is not known precisely how myelin is formed in either PNS or
CNS. Akt/mTOR (mammalian (or mechanistic) target of rapamycin)
signalling has emerged as one of the major pathways involved in myeli-
nation; it has been implicated in the regulation of several steps during
the development of myelinating Schwann cells and oligodendrocytes
(Norrmén and Suter 2013). In the CNS, myelination also depends in
part on expression of a protein (Wiskott–Aldrich syndrome protein
B family verprolin homologous; WAVE), which influences the actin
cytoskeleton, oligodendrocyte lamellipodia formation and myelination


Fig. 3.14 A, An oligodendrocyte enwrapping several axons with myelin, (Kim et al 2006). The ultrastructural appearance of myelin is usually
demonstrated in a whole-mounted rat anterior medullary velum, explained in terms of the spiral wrapping of an extensive, flat glial
immunolabelled with antibody to an oligodendrocyte membrane antigen. process (lamellipodium) around an axon, and the subsequent extrusion
B, A confocal micrograph of a mature myelin-forming oligodendrocyte in of cytoplasm from the sheath at all points other than incisures and
an adult rat optic nerve, iontophoretically filled with an immunofluorescent paranodes. In this way, the compacted external surfaces of the plasma
dye by intracellular microinjection. (A, Courtesy of Fiona Ruge. membrane of the ensheathing glial cell are thought to produce the
B, Prepared by Professor A Butt, Portsmouth, and Kate Colquhoun, minor dense lines, and the compacted inner cytoplasmic surfaces, the
formerly Division of Physiology, GKT School of Medicine, London.) major dense lines, of the mature myelin sheath (Fig. 3.16). These lines,
first described in early electron microscope studies of the myelin sheath,
correspond to the intraperiod and period lines respectively, defined in
X-ray studies of myelin. The inner and outer zones of occlusion of the
spiral process are continuous with the minor dense line and are called


NERvOuS SySTEm
52
1
NOITCES
Fig. 3.16 Suggested stages in
myelination of a peripheral axon by an
ensheathing Schwann cell.
Schwann cell Basal Inner Outer
cytoplasm lamina mesaxon mesaxon Axon
the inner and outer mesaxons. For further reading on aspects of myeli-
nation, see Bakhti et al (2013). V
There are significant differences between central and peripheral
myelin, reflecting the fact that oligodendrocytes and Schwann cells
express different proteins during myelinogenesis. The basic dimensions
of the myelin membrane are different. CNS myelin has a period repeat C
thickness of 15.7 nm whereas PNS myelin has a period to period line
E
thickness of 18.5 nm, and the major dense line space is approximately
1.7 nm in CNS myelin, compared with 2.5 nm in PNS myelin. Myelin
membrane contains protein, lipid and water, which forms at least 20%
of the wet weight. It is a relatively lipid-rich membrane and contains SVZ
70–80% lipid. All classes of lipid have been found; perhaps not surpris-
ingly, the precise lipid composition of PNS and CNS myelin is different.
The major lipid species are cholesterol (the most common single mol-
ecule), phospholipids and glycosphingolipids. Minor lipid species
include galactosylglycerides, phosphoinositides and gangliosides. The
major glycolipids are galactocerebroside and its sulphate ester, sul- Fig. 3.17 Ciliated columnar epithelial lining of the lateral ventricle (V),
phatide; these lipids are not unique to myelin but they are present overlying the subventricular zone (SVZ). C, cilia; E, ependymal cells.
in characteristically high concentrations. CNS and PNS myelin also Mouse tissue, toluidine blue stained resin section.
contain low concentrations of acidic glycolipids, which constitute
important antigens in some inflammatory demyelinating states. Gan-
gliosides, which are glycosphingolipids characterized by the presence ependymal lining of the ventricles but four major types have been


of sialic acid (N-acetylneuraminic acid), account for less than 1% of the described. These are: general ependymal, which overlies grey matter;
lipid in myelin. general ependymal, which overlies white matter; specialized areas of
A relatively small number of protein species account for the majority ependyma in the third and fourth ventricles; and choroidal epithelium.
of myelin protein. Some of these proteins are common to both PNS The ependymal cells overlying areas of grey matter are cuboidal.
and CNS myelin, but others are different. Proteolipid protein (PLP) Each cell bears approximately 20 central apical cilia, surrounded by
and its splice variant DM20 are found only in CNS myelin, whereas short microvilli. The cells are joined by gap junctions and desmosomes.
myelin basic protein (MBP) and myelin associated glycoprotein (MAG) Beneath them there may be a subependymal (or subventricular) zone,
occur in both. MAG is a member of the immunoglobulin supergene from two to three cells deep, consisting of cells that generally resemble
family, and is localized specifically at those regions of the myelin ependymal cells. In rodents, the subventricular zone contains neural
segment where compaction starts: namely, the mesaxons and inner progenitor cells, which can give rise to new neurones, but the existence
periaxonal membranes, paranodal loops and incisures, in both CNS of these stem cells in the adult human brain is controversial (Sanai et al
and PNS sheaths. It is thought to have a functional role in membrane 2011, Kempermann 2011). The capillaries beneath the ependymal cells
adhesion. have no fenestrations and few transcytotic vesicles, which is typical of
In the developing CNS, axonal outgrowth precedes the migration of the CNS. Where the ependyma overlies myelinated tracts of white
oligodendrocyte precursors, and oligodendrocytes associate with and matter, the cells are much flatter and few are ciliated. There are gap
myelinate axons after their phase of elongation; oligodendrocyte myelin junctions and desmosomes between these cells, but their lateral margins