The central nervous system (CN S) is composed of various
types of cell including neurons, glial cells (astrocytes, oligodendrocytes,
ependyma and choroid plexus epithelium), blood vessel elements and microglia.
Leptomeninges (pia mater and arachnoid mater) surround the CNS, and the
pachymeninges (dura mater) form an outer coating which separates the brain from
'the skull and the spinal cord from the spine.
An under-standing of the basic structure and function of the
different cell types in the brain and spinal cord is a prerequisite for an
appreciation of the pathology of the nervous system.
Nerve cells vary enormously in size and configuration. The
cerebellum presents the best example of morphological extremes: the Purkinje
cells and their impressive dendritic trees dwarf the neighbouring granule cells
and their short dendrites.
The shape of the nerve cell body, the perikaryon, also
varies throughout the central nervous system: pyramidal, polygonal, round, oval
and fusiform forms can be distinguished. Neuronal cell processes fall into two
categories: dendrites and axons. Whilst a neuron usually has only a single
axon, the number of dendrites ranges from one to nearly one hundred. The length
and arborisation of processes also display considerable individual variations.
Silver impregnation techniques of classical neurohistology, electron microscopy,
enzyme histochemistry and more recently immunocytochemistry have all
contributed to the understanding of neuronal morphology and function. The
previous morphological classifications of nerve cells are now gradually being
replaced by classifications based on functions: neurons can be distinguished
according to the neurotransmitters they use.
Nerve cell nuclei are round or oval, although the nuclear
profile is occasionally indented. The karyoplasm is separated frorn the cytoplasm by the nuclear
membrane which is composed of two laminae enclosing the perinuclear cisterna:
the inner lamina is smooth, whilst the outer one, studded with ribosomes, is
frequently continuous with the rough endoplasmic reticulum. Finely granular
chromatin is evenly dispersed with some clumping at the nuclear membrane .
The nucleolus is prominent and this helps to distinguish
neurons from astrocytes which contain only a small inconspicuous nucleolus.
Electron microscopy reveals the nucleolus to be composed of granular and
fibrillar constituents. Attached to the nucleolus is the nucleolar satellite or
sex chromatin: a dense, coarsely fibrillated body which occurs only in females.
Nuclear inclusions of various types, filamentous,
granulofibrillar, tubular and vesicular,' often occur in normal neurons and can
be occasionally discerned in the light microscope. Variations in nuclear
morphology exist according to neuronal type, topography and functional
activity. The large vesicular nuclei of the Purkinje cells or the pyramidal
cells of the cerebral cortex are in sharp contrast to the small, dense nuclei
of the cerebellar granule cells.
This cytoplasmic component is intensely basophilic when
stained with cresyl violet or methylene blue. Electron microscopy shows that
Nissl substance is composed of stacks of the rough-surfaced endoplasmic
reticulum (RER) . The cisternae are usually arranged in parallel arrays and
their outer surface is covered by ribosomes. The amount of RER varies from
neuron to neuron and appears to be related to the length of the axon: it is particularly
abundant in the anterior horn cells of the spinal cord and the pyramidal
neurons of the cerebral cortex. It is present not only in the perikaryon but
also in the dendrites, but it is absent from the axon hillock and from the axon
itself. Since the RER is the site of protein synthesis, its amount is related
to the metabolic activity of the cell. The Nissl substance forms an integral
component of the neuronal membrane system which is associated with the transfer
of membrane molecules amongst organdies, the packaging and transport of
exportable protein and energy metabolism. In addition to the membrane-bound particles of the RER,
ribosomes are scattered throughout the cytoplasm either singly or in groups as
polyribosomes or ribosomal rosettes.
Although the precise function of the agranular reticulum is
not known, its widespread distribution within the cytoplasm and its close
spatial relationship to the cell membrane suggest a role in intracellular
transport.
The internal reticular apparatus of Golgi appears as
tortuous anastomosing strands in the light microscope. Located between the
nucleus and the cell membrane or at the base of a dendrite, the Golgi apparatus
is composed of arrays of closely packed, smooth-surfaced cisternac and numerous
associated vacuoles and vesicles. Its curved configuration allows a convex,
external forming face and a concave, internal mature face to be distinguished.
The internal face of the Golgi apparatus forms an integral part of the GERL
system (Golgi apparatus, smooth endoplasmic reticulum and lysosomes): a
spatially closely related group of organelles which is devoted to the
synthesising and condensing activity of the Golgi apparatus. This polarisation of the Golgi
apparatus, although not evident in all neurons, is thought to serve the
efficient transport of materials. The demonstration of concanavalin A binding
sites on Golgi membranes strongly suggests that this organelle is concerned
with glycoprotein metabolism. The formation of new plasma membranes
during mitosis and the maintenance of normal membrane structure in resting
cells are important functions of the Golgi apparatus.
The Golgi apparatus itself promotes the movement of
membranes: vacuoles fuse to form a cisterna at the forming face, while vesicles
are budding off at the mature face. The diameter of these vesicles ranges from
20-60 mm and they are usually smooth-surfaced, round or elliptical.
Coated or alveolate vesicles of 50-60 mm diameter are distinguished by their regu]arly spaced arms
or striac. These vesicles are concerned with the transport of hydrolytic
enzymes to the lysosomal system. Larger alveolate vesicles, 100mm in
diameter, derived from the cell surface by invagination or pinocytosis, ingest
proteins which then are transferred to the lysosomes to be digested. In addition,
many neurons, particularly those of the supraoptic and paraventricular nuclei,
contain dense-cored, neurosecretory granules up to -150 mm in
diameter.
Multivesicular bodies are spherical structures of 0.5 mm in
diameter which contain vesicles and an assortment of inclusions. Although
frequently associated with the Golgi apparatus, they are not part of these
organelles and occur throughout the perikaryon and cell processes.
Multivesicular bodies sequester material transported to them by coated
vesicles, and hydrolytic enzymes acquired from smaller coated vesicles convert
them into lysosomes.
Primary lysosomes are round or oval, uniformly dense bodies
up to 1 mm in
diameter, bound by a unit membrane. They contain various hydrolytic enzymes,
including acid phosphatase which serves as a marker enzyme for their
identification. Secondary lysosomes are larger, more irregular and usually
contain various ingested materials.
Although visible by light microscopy, lipofuscin can be
better appreciated in the electron microscope: a single membrane encloses a
dense granule and one or two peripheral vacuoles. Lipofuscin or lipochrome is
frequently referred to as 'wear-and-tear' pigment, since the number of granules
within the neurons increases with age. These granules are end products of
intracellular peroxidation and polymerisation of unsaturated fatty acids. Their
origin is controversial, but according to the most widely accepted concept they
are derived from lysosomes. The precise function of lipofuscin is unknown.
Degenerated cytoplasmic
constituents contribute to
its formation, which requires intracellular oxidants and antioxidants.
Lipofuscin is thus the byproduct of metabolic activity; it is stored in lysosomes
and is only disposed of by expulsion during mitosis or by cell death. Since mature nerve cells do not divide,
lipofuscin granules accumulate during life. Appearing as light brown granules
in haematoxylin and eosin stained sections, lipofuscin can be demonstrated by
a variety of fat stains including Sudan black B, Sudan III and Nile blue
sulphate. It is acid fast and PAS positive and reduces ferric ferricyanide to
Prussian blue (Schmorl's reaction).
This pigment is present in the leptomeningeal cells and in
the pigmented nuclei of the brainstem. Melanin-containing cells in the
leptomeninges are most plentiful over the ventral aspect of the brain-stem;
this is the area in which the rare primary malignant melanomas most often
develop. Two major accumulations of pigmented neurons occur in the brainstem:
in the substantia nigra of the midbrain and in the much smaller locus ceruleus
of the pontine tegmentum. The cells of the substantia nigra and locus ceruleus
are dopaminergic and noradrenergic
respectively. Other brainstem
nuclei, including the motor nucleus of the vagus, also contain melanin in small
amounts.
These organelles vary considerably in shape and size,
depending upon their location within the neurons. They are apparently
distributed at random in the perikaryon and also occur in dendrites and axons,
including the presynaptic terminals. Mitochondria have a smooth outer membrane
and an irregular inner membrane. The inner membrane forms complex folds
(cristae); the inner compartment of the mitochondrion is filled with a
moderately dense matrix. The inner surfaces of the cristae are rendered uneven
by many minute projections, each ending in a knob. The inner and outer
membranes differ in composition, structure and function; the electron transport
mechanism and many hydrogenases are located in the inner membrane, whereas the
monoamine oxidase system is found in the outer membrane.
The neuronal cytoskeleton is composed of three
elements: neurofilaments, microtubules and microfilaments.
Neurofilaments.
These filaments are 10 mm in diameter and of indeterminate length. They belong to the class of intermediate filaments, their diameter being in between that of the micro-filaments (4-6 mm) and that of microtubules (24 mm). Of the five types of intermediate filaments found in animal cells, two occur in the central nervous system: neurofilaments in nerve cells and glial filaments in astrocytes. Although the various types of intermediate filaments appear to be similar morphologically, they are composed of different proteins.
In cross-section, neurofilaments display a central hollow
core surrounded by a wall of 3 mm in
thickness. The basic unit of the wall is composed of four globular subunits,
each 3.5 mm in
diameter, which are linked together by connecting arms of 2.5 mm in
thickness. These units are stacked one upon another and rotated in the
transverse plane by 45° to each
other. In longitudinal section, neurofilaments appear as two dense,
parallel lines which enclose the central hollow core. They are dispersed
throughout the perikaryon, but tend to accumulate at the base of large
processes, into which they extend, forming parallel arrays.
Neurofilaments isolated from the nervous system are formed
by three polypeptides with the approximate molecular weights of 70, 150 and 200
kilodaltons. Recent investigation has revealed that
immunohistochemical differences may exist between neurofilaments in the
perikarya, dendrites and axons.
Although the morphology and biochemistry of neurofilaments
have been established, very little is known about their functions.
They are intimately related to microtubules, the other component of the
neuronal cytoskeleton, and with them they could play a role not only in
stabilising nerve cells, but also in axonal transport. Neurofilaments are also major intrinsic determinants
of axonal diameter in large myelinated nerve fibres: the expression of a single
set of neuron-specific genes encoding neurofilaments directly determines axonal
calibre."
Microtubules.
Microtubules
are of indeterminate length and
24mm in
diameter. Their walls are 6 mm thick
and composed of 13 globular subunits, each representing a constituent protofilament.
Microtubules are
intermingled with neurofilaments both in the penkaryon and in cell processes:
the ratio of neurofilaments to micro-tubules decreases as the axon becomes
smaller, and in thin unmyelinated axons usually only micro-tubules are present.
Tubulin is the major protein component of microtubules. In an adult brain this
protein comprises 10-30 of the soluble protein and more recently a group of microtubule-associated proteins
has also been recognised. Many
functions have been attributed to microtubules: skeletal support, maintenance
of axonal flow, transport of various substances and of cytoplasmic vesicles,
cellular contraction and a role in mitosis. Microtubules also play a role in the maintenance and function of
the Golgi apparatus.
Microfilaments.
These are not obvious in nerve cells: they have a diameter
of 4-6 mm and are
composed of actin, a globular protein with a molecular weight of 42000. Microfilaments,
in addition to their stabilising function, also play a role in axonal
transport.
Synapses are specialised interneuronal contacts which can be
electrical or chemical. Electrical synapses function by the propagation of
electrical impulses and do not require elaborate structural organisation of the
plasma membrane and cytoplasmic organelles. These synapses, which are rare in
mammals but common in lower vertebrates, are formed by the close apposition of
the cell membranes at a gap junction. Chemical synapses, in contrast, utilise
various substances-neurotransmitters and neuropeptides-for intercellular
communication: this chemical
transmission requires a sophisticated subcellular mechanism well
demonstrated by electron microscopy. By light microscopy, using silver
impregnation techniques, only the profile of the end-bulb or bouton terminal
of the axon abutting onto the surface of the perikaryon or dendrite can be
seen. A synapse is composed of three constituents: the presynaptic element, the
synaptic cleft and the postsynaptic component. Both the pre- and the
postsynaptic membranes display densities along the specialised stretch of cell
membrane and these, together with the intervening cleft, are referred to as the
synaptic junction.
Originally two types of synapse were distinguished on
ultrastructural examination of the pyramidal cells of the cerebral cortex. The
type I junction is usually extensive, the postsynaptic density prominent,
rendering the synapse asymmetrical, and the wide synaptic cleft contains a
dense plaque. In the type II synapse, in contrast, the postsynaptic density is
less readily identifiable and the narrower cleft does not contain a dense
plaque; the overall configuration is symmetrical. The presynaptic element in
most cases is an axon, either at its end (bouton terminal) or along its course
(bouton en passant): the axonal terminal can form a synapse with any part of
another neuron and thus axo-dendritic, axo-somatic and axoaxonal synapses are
distinguished. The presynaptic element, however, does not need to be an axonal
terminal and synapses can be formed between any part of two neurons, providing
a wide variety of synapses.
The presynaptic element contains the synaptic vesicles which,
in turn, are filled with neurotransmitters. The size, shape and content of the
vesicles vary, depending upon the type of synapse. The most frequently occurring
vesicles are apparently clear, spherical and 40-50 mm in
diameter. Elongated or flattened vesicles with clear centres are 20 mm wide and
50 mm long.
There have been many attempts to correlate vesicular shape with functional
activitv:
spherical vesicles occur in excitatory, type I synapses,
whilst flattened vesicles are associated with inhibitory, type II synapses.
Larger vesicles of up to 60 mm in
diameter with a dense core are encountered in areas of catecholamine activity
and contain noradrenaline, dopamine or 5-hydroxy-tryptamine. Another, larger
dense-cored vesicle, up to l50 mm with a
spherical dense core of 50-70 mm in
diameter, is most frequently seen in the presynaptic terminals of autonomic
ganglia, but also occurs in various parts of the central nervous system
intermingled with clear vesicles. The presynaptic element, particularly the
axonal terminal, also contains other organelles, including mitochondria, neurofilaments, microtubules, smooth endoplasmic reticulum and glycogen.
The synaptic cleft, separating the pre- and postsynaptic
membranes, is 20-30 mnm wide
and usually contains a dense plaque of intercellular material. In addition,
filaments appear to traverse the cleft and contribute to the formation of the
plaque.
The
postsynaptic membrane is
rendered conspicuous by an accumulation of dense material on its cytoplasmic
surface. This post-synaptic density, composed of granular material and an
occasional filamentous structure, is more pronounced in asymmetrical, type I,
synapses. The existence of postsynaptic density is dependent upon the presence
of the presynaptic element: if the
presynaptic structures degenerate,
the postsynaptic density will eventually disappear. The postsynaptic
element also contains cisternae of the smooth endoplasmic reticulum and the
spine apparatus, which is composed of 2-3 flattened cisternae, separated by
plaques of dense material.
The morphological appearances of synapses reflect the
functional dynamics of neurotransmission. Accordingly, in
chemical synapses the vesicles contain quanta of the neurotransmitter which is
discharged into the synaptic cleft after the vesicle has fused with the
presynaptic membrane. Thus, the uptake of calcium into the nerve terminal
triggers off a chain of events leading to exocytosis: vesicular apposition,
membrane fusion and fission. Although
this vesicular or exocytotic hypothesis of neurotransmission provides a plausible explanation for
the quantal nature of
transmitter release, an increasing body of evidence now
suggests that this may not be the only mechanism by which chemical signals in
the central nervous system are propagated. Chemical substances may be released
from non-synaptic axon terminals and even from regions of nerve cells other
than presynaptic axon.
The mechanism of exocytosis itself remains poorly understood
not only morphologically, but also neurochemically.