Synapses
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 matnmals 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 (Fig. 1.5). Both the pre- and the postsynaptic membranes display
densities along the speci~ised 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.15
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 (Fig.
1.5). 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 nm in diameter. Elongated or flattened vesicles with
clear centres are 20 nm wide and 50 nm long. There have been many attempts to
correlate vesicular shape with functional activity: spherical vesicles occur in
excitatory, type I synapses, whilst flattened vesicles are associated with
inhibitory, type II synapses. Larger vesicles of up to 60nm 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
lSOnm with a spherical dense core of 50-70 nm 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 20-3Onm 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 (Fig. 1.5). 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 ~so contains cisternac of the smooth
endoplasmic reticulum and the spine apparatus, which is composed of 2-3
flattened cisternac, 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.16 Although this vesicular
or exocytotic hypothesis of neurotransmission'7 provides a plausible
explanation for the quantal nature of
transmitter release, an increasing body of evidence now suggests that
this mav 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.
A parasynaptic system is envisaged
in which so-called neuroactive or informational substances reach specific
target cell receptors by diffusion from release points through the
extracellular space. The mechanism of exocytosis itself remains poorly
understood not only morphologically, but also neurochemically, and various
alternative biochemical mechanisms have been considered to explain the release
of neurotransmitters.
Neuronal processes
AXONS
The transitional
zone between the neuronal perikaryon and the axon is the cone-shaped axon
hillock. In larger, multipolar neurons the axon hillock lacks Nissl substance,
and it is in this region that cytoskeletal elements, the microtubules and
neurofilaments, converge to become parallel as they enter the axon. The
microtubules then form a fascicle in the initial segment of the axon, a feature
'vhich enables axons to be distinguished from dendrites, in which microtubules
are more evenly distributed. The more distal portion of the axon may contain
various organelles, but granular endoplasmic reticulum and polyribosomes are
usually absent. The internal structure of the axon has recently been visualised
as a three-dimensional lattice: the longitudinally orientated neurofilaments
and microtubules are extensively cross-linked to each other and to the plasma
membrane by thin filaments. Similar bridges also connect membrane-bound
organelles with the components of the cytoskeleton and with each other .There
is axonal transport of material from the perikaryon towards the periphery
(anterograde transport) and to a lesser extent in the opposite direction
(retrograde transport). Since the axon terminal, the most active
site of neurotransmission, can be far removed from the perikaryon in which
proteins are synthesised, this axonal transport is vital for the proper
functioning of the nerve cell. Axonal flow has a slow and a fast component,
0~2-8~0mm and 50-500 mm per day respectively. Fast axoplasmic flow carries
organelles, including vesicles and mitochondria, and membrane-bound substances
like proteins and neurotransmitters
materials which are essential for synaptic activity. The fast axonal
flow is effected by microtubules, but the possibility that some membrane-bound
proteins are transported by the smooth endoplasmic reticulum Or
another tubulo-vesicular system cannot be excluded. Slow flow,
in contrast, transports high molecular weight and soluble materials which are
involved in the growth and maintenance of the axon. The structural basis of
slow transport is controversial, but the movement of the cytoplasmic matrix
itself may represent the prime force.23 Mechanisms of anterograde
and retrograde transport are similar: both need metabolic energy, have similar
ionic requirements and are sensitive to the same drugs.23 Both
anterograde and retrograde transport can be blocked by low temperatures and
suspended by colchicine and vinblastine, agents which disrupt microtubules. The
factors which determine the direction of axonal transport remain conjectural:
alternatives envisage either two, oppositely polarised transport systems or a
single mechanism in which the direction of movement is determined by the nature
of the material or organelle to be transported. Investigation of the molecular
mechanisms of axonal transport should contribute to our further understanding
of this vital neuronal function.
Dendrites
There
is wide variation in the number and organisation of these cell processes in the
central nervous system. The character of the dendritic tree reflects the
afferent neuronal connections and consequently indicates the functional
activity of the cell. The complex configuration of dendrites is best
appreciated in Golgi preparations; these have allowed the classification of neurons
into three groups based on their dendritic arborisations (Fig. 1.1).
Isodendritic neurons issue straight dendrites which run in all directions,
whilst allodendritic cells are distinguished by shorter, branched dendrites
which are restricted in their wavy course. Idiodendritic neurons have a unique
dendritic tree characteristic of
and determined by
their location.27 A further, more detailed classification of
neurons has been achieved by the dendritic branching pattern.
Although clear differences exist, it
may not be always easy to distinguish a dendrite from an axon. Dendrites have
irregular contours, taper gradually, branch at relatively acute
angles, are unmyelinated and contain Nissi substance. Axons, in contrast,
display a smoother contour, have a relatively even diameter along their course,
branch at obtuse or at right angles, can be myelinated or unmyclinated and lack
Nissl substance. The smaller axons and dendrites become, the more difficult is
their positive identification; the presence of clustered ribosomes,
particularly in association with cisternac of rough-surfaced endoplasmic
reticulum, remains the most reliable identifying feature of small dendritic
processes.
The dendritic tree represents the
most substantial receptive area of the nerve cells Synapses are formed either
on the dendritic trunks themselves or on the dendritic spines, the specialised
structures projecting from them. The spines are composed of a stalk or neck
which connects the dendrite with the ovoid bulb or head. There is a
considerable variation in their configuration, but their overall length appears
to be relatively constant at 2 um. Spines can also be present on the
perikaryon and they are responsible for 43()() of the total surface area of the
dendrites and the cell body: there are 4000 spines on a single pyramidal
neuron.~ The function of the dendritic spines is still largely unknown.
Although they synapse with axon terminals, their role is not restricted to
increasing receptive surfaces; they may regulate the excitatory input to a
neuron.1
The neuropil and the extracellular
space
The
neuropil is composed of the complex and intricate network of neuronal cell
processes. This intermingling and interconnection of myelinated and
unmyelinated axons and dendrites may appear random, but these processes form
the neuronal circuitry of a particular area. Cell processes of astrocytes,
oligodendrocytes and microglial cells further add to the variety of structures
in the neuropil (Fig. 1.3).
Cell processes and perikarya, bounded
by typical unit membranes, are separated by an extra-cellular space with an
average width of 15-20 run. Electron-dense markers, electrical impedance and
the distribution of radiotracers have conclusivelv demonstrated the existence
of this extracellular space, which constitutes 18~25o() of the total gre~' and
white matter.29
Myelin
Myelin
in the central nervous system is produced by oligodendrocytes (see p. 22-24).
The myclin sheath is formed by the spiral wrapping of the cytoplasmic processes
of the myelinating cells around axons, and the subsequent extrusion of the
cytoplasm leads to a compact, tightly spiralled, multi-layered envelope. Electron microscopy reveals the
characteristic structure of the myelin sheath: major dense lines alternate with
thinner intraperiod lines to form the repeating units. The major dense line
results from the fusion of the thicker, inner leaflet of the oligodendrocytic
plasma membrane, whereas the intraperiod line is formed by the apposition of
the thinner, outer leaflet of this membrane. Unlike Schwann cells (the
myelinating cells of the peripheral nervous system which are concerned with the
myelination of a single axon), each oligodendrocyte may provide myelin for many
axons. From this it follows that the motion by which the sheath is produced by
the myelinating cell may be different in the central and peripheral nervous
Systems. Whilst Schwann cells can, in principle, lay down myelin by rotating
around a single axon, the oligodendrocyte, being in connection with many axons,
cannot perform a revolving motion. Consequently, ensheathment takes place by
the progressive lengthening of the oligodendrocytic process which encircles the
axon completely and an internal mesaxon is formed by apposition of the free
edges of the myclinating process. The outermost lamella of the sheath encloses
the outer tongue and this, together with the internal mesaxon, represents the
tenuous connections which remain between the fully formed myclin and the
myelinating cell.
Nodes of Ranvier occur regularly
along the course of central myclinated fibres; the segment between two nodes is
referred to as internodal myclin, and the region where the lamellae terminate
is the paranode. The thickeness of the myelin sheath is related to axonal
diameter: larger axons are surrounded by thicker myelin sheaths. Evidence from
experimental animals has convincingly shown that the formation of myelin is
preceded by the proliferation of glial precursors which develop into young
oligodendrocytes. The processes of these active oligodendrocytes are frequently
wrapped around axons, but this direct connection is difficult to demonstrate in
later life.' Biologically, the formation of myclin is a two-step process:
first, the oligodendrocyte relates to the axon in response to an axonal
myelinogenic stimulus and, second, it produces myelin, the volume of which is
determined by the internodal axonal surface area. 30
Mvelination in man progresses slowly
and generally proceeds centripetally: it commences peripherally and whilst many
axons, particularly in the spinal cord) are myclinated at birth, the more
central fibres in the frontal and parietal lobes remain unmyclinated well into
posmatal life. Completion of myelin formation is achieved largely during the
first two years after birth.31 Immunohistochemistry for myelin basic
protein confirms earlier findings of the chronological sequence of myelination:
phylogenetically older regions acquire myelin first.32 The
sequential nature of myelination reflects physiological demand: the time and
rapidity of myelination are related to the relative significance of a fibre
system at various periods of cerebral development.
Biochemically, myelin is composed of
alternating layers of proteins and lipids. Of the myelin proteins, a proteolipid
protein constitutes approximately 50 mu, basic protein (the antigenic agent
capable of inducing experimental allergic encephalomyclitis) 30%, and an acidic
proteolipid protein 200/0 .3' Myelin-associated glycoprotein is an acidic,
concanavalin A binding minor component which is also present in the cytoplasm
of oligodendrocytes before and during myelination. The various lipids to be
found in the myelin include cholesterol, phosphatidylethanolamine,
phosphatidylserine and phosphatidylcholine, sphingomyelin and
glycolipids. Galactocerebroside
is the main glycolipid component and the cell membrane of the myelinating cell
contains a high percentage of this compound. This suggests that
galactocerebroside may play an important role in the successive layering of
cell membranes, a
process
unique to myelination.