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1
ORGANIZATION OF THE NERVOUS SYSTEM
Table 1.10 Comparison of autonomic nervous system divisions
Sympathetic Parasympathetic
Afferent cell
body location
Peripheral
innervation
Preganglionic
cell body
location
Postganglionic
cell body
location
Preganglionic/
postganglionic
fibre ratio
Neurotransmitter Acetylcholine Acetylcholine
Neurotransmitter
receptors
Preganglionic Nicotinic
Postganglionic Adrenergic (α1,
Function Alarm and arousal
Table 1.11 General effects of blocking cholinergic or adrenergic
Site of action
Heart Tachycardia Bradycardia
Eye Pupil dilatation, paralysis
Gastrointestinal
tract
Bladder Urinary retention Incontinence
Sweat glands Decreased sweating
Salivary glands Dry mouth Dry mouth
Arterioles Vasodilatation Vasoconstriction
Veins Venodilatation Venoconstriction
T1–L2 spinal
ganglia
Skin, blood vessels
and viscera
throughout
body
Intermediolateral
horn of T1–L2
spinal cord
Paravertebral and
prevertebral
chain ganglia
1:17—widespread
effects
Adrenaline
cholinergic
α2, β1, β2, β3)
(muscarinic,
cholinergic at
sweat glands)
system (fight,
flight and fright)
receptors
Effect of cholinergic
receptor blockade
of accommodation
Decreased tone,
secretion and
motility constipation
and warm skin
Cranial nerve sensory
ganglia (V, VII, IX, X)
Spinal nerve ganglia S2–
S4 (splanchnic nerves)
Limited to head (lacrimal,
salivary glands and eye
muscles) and viscera of
chest, abdomen and
pelvis
Brainstem and
intermediolateral horn
of S2–S4 spinal cord
Near or in peripheral
target organ
1:2—localized effects
Nicotinic cholinergic
Muscarinic cholinergic
Homeostasis (rest and
recuperation or growth,
immunity, digestion and
energy conservation)
Effect of adrenergic
receptor blockade
Pupil constriction
Decreased gluconeo-
genesis, increased
tone and motility
Decreased sweating
and warm skin
Table 1.12 Signs of autonomic nervous system dysfunction
Sign Cause
Postural
hypotension
Tachycardia Defective sympathetic nervous system activity
Impotence Bladder and sexual dysfunction reflect
Bladder/bowel
dysfunction
Anhydrosis Diminished or no sweating is most pronounced
Postural hypotension reflects dysfunction of the
baroreflex pathways, either the afferent limb
in the vagus nerve or the efferent limb in the
splanchnic nerves
demyelination of preganglionic fibres
distally and reflects involvement of postganglionic
sympathetic fibres to sweat glands
Parasympathomimetic drugs are also used to treat urinary
incontinence or stimulate bowel function after surgery.
Clinical signs and symptoms of autonomic nervous
system dysfunction
Autonomic dysfunction may occur due to a disease process that is selective for ANS cells and fibres, as seen in
pure autonomic failure, multiple system atrophy (Shy–
Drager syndrome) and genetically acquired syndromes
such as familial dysautonomia (Riley–Day syndrome).
It may also be secondary to other medical conditions,
as in Parkinson’s disease, diabetes, infectious peripheral
neuropathy, alcoholism, multiple sclerosis and spinal
cord damage. The cardinal signs of ANS dysfunction are
detailed in Table 1.12.
In peripheral neuropathies such as Guillain–Barré
syndrome (Box 2.2), these signs are accompanied by distinct signs of peripheral nerve damage. The initial signs
are distal paraesthesia, numbness and muscle weakness, muscle wasting and decreased stretch reflexes,
but no fasciculation. The autonomic signs develop more
slowly and become prominent as the weakness advances
proximally.
Diabetes is the most common cause of peripheral neuropathy with ANS involvement. The early compromise
of small- diameter axons leads to distal loss of pain and
temperature sensation, which precedes loss of vibration
and position sense. Sweating is impaired and blood flow
to the affected region is increased due to sympathetic
denervation. The latter signs appear before the somatic
sensory signs. Gustatory sweating—abnormal sweating
of the face, scalp and neck that starts within a few minutes of starting to chew food—is common in diabetic
peripheral neuropathies.
Multiple sclerosis and spinal cord lesions disrupt
ANS function by disconnecting the preganglionic neurons from its supraspinal control. The effects depend on
the level and severity of the lesion. Complete spinal cord
transection is devastating to body temperature control,
blood pressure regulation and bowel, bladder and sexual
function.
29THE NERVOUS SYSTEM
1
The ENS is the largest division of the ANS, comprising hundreds of millions of neurons. It innervates the
oesophagus, stomach, intestine, pancreas and gallbladder, and is composed of two plexuses, the myenteric and
submucosal, which register changes in the tension of
the gut wall and the chemical composition of the stomach and intestinal contents, to control the process of food
digestion and transportation for excretion. It is a functionally separate system that works independently of the
sympathetic and parasympathetic systems, but because
of the large numbers of neurons, it acts as a ‘second
brain’ to independently control gut functions, so that the
cortex does not have to accommodate all these neurons
and associated circuitry. Many neurotransmitters, anatomical connections and signalling pathways are common between the CNS and ENS, and there is a two- way
communication process between the two systems. This
has prompted the idea that, since they share neuronal
and immune pathways, this can allow diseases to spread
ORGANIZATION OF THE NERVOUS SYSTEM
from the gut to the brain (e.g. along the vagus nerve);
many CNS conditions also present with ENS deficits.
Currently, much research is focused on the gut- brain axis
and its roles in neurological conditions, such as autism,
amyotrophic lateral sclerosis, Parkinson’s disease and
Alzheimer’s disease.
Congenital abnormalities in the ENS system lead to
Hirschsprung’s disease (megacolon), characterized by
an absence of ganglion cells in the myenteric plexus.
Sufferers have an enlarged colon and the major symptom is constipation. Surgical intervention is required to
remove the affected part of the colon.
Putting it all together: from anatomy to
behaviour
To produce behaviour, external sensory inputs are
relayed from the periphery to the brain, which then integrates and assesses the information to produce a motor
response. This principle can be extended down to lower
organizational levels, such as the nucleus (e.g. brainstem
nuclei provide input to the thalamic nuclei that is then
relayed to different cortical nuclei) and the individual
neuron (where inputs from individual fibres converge
onto a single neuron, which then integrates the information and passes it to other neurons).
Sensory and motor systems exist at all levels of the
nervous system. Peripheral nerves have sensory and
motor components, and these separate in the CNS to
become specialized grey matter areas and nuclei associated with either sensory or motor functions. These specific functions are then relayed to separate areas in the
cerebral cortex where they are separated in two ways: a
specific primary area for discrete sensations within cortex lamina 4 always receives sensory input, while laminae 5 and 6 provide motor output (the other cortical
layers are integrative in function).
An important but unexplained feature of the organi-
zation of the brain is that most pathways are bilaterally
symmetrical, and they cross from one side of the nervous
system to the other. Thus each cortex receives sensory
input from the opposite side of the body and controls the
movement of the contralateral side. Different pathways
cross at different levels. For example, the pain pathway
crosses in the spinal cord, whereas the pathway for voluntary control of movement crosses at the junction of the
brainstem and spinal cord. Crossing in the visual system
is more complicated (see Chapter 7). One problem posed
by this organization is that information reaching one side
of the body has to be integrated with information reaching the other side. This occurs via commissural pathways, which contain only axons crossing from one side
of the brain to the other. The most prominent and largest
of these is the corpus callosum, which connects the frontal, parietal and occipital lobes on each side; the anterior
commissure connects the temporal lobes on either side.
Although the brain is anatomically symmetrical in
some respects, in terms of some functions the brain is
asymmetrical. This is certainly true of higher mental
functions such as control of speech or spatial navigation.
In order to produce behaviour, neuronal circuits are
regulated by coordinated excitation and inhibition. This
principle applies to both single neurons and groups of
neurons (nuclei). Neurons pass information to each other
by being switched ‘on’ or ‘off’ by the appropriate neurotransmitter or combinations of neurotransmitters (neurons release mostly one neurotransmitter, but cases of
co- release of different neurotransmitters do occur in the
nervous system, and the implications of this phenomenon are still incompletely understood).
At the level of circuits, consider the role of the basal
ganglia in movement. One of its functions is to scale the
activity of the thalamic nuclei in regulating the size of
the movement. Damage to the basal ganglia affects the
activity of the thalamus and results in altered, abnormal
movements; damage to one nucleus produces increased
movement, while damage to another produces the opposite effect (see Chapter 10). This is analogous to the
actions of the sympathetic and parasympathetic nervous
systems; that is, one is excitatory, and the other is inhibitory for a given function (see Table 1.10).
The multiple levels of function seen in the nervous
system are a product of evolution. As the brain evolved,
new areas were added to the preexisting ones. Consider
the evolution of movement: fish have no legs and use
whole- body movements to swim, controlled by the spinal cord and hindbrain. Amphibians developed legs
and control regions in the brainstem. Humans developed the ability to walk on two legs and independent
control of limbs and digit movement, requiring further
control areas, which are housed in the forebrain. For
sensory areas, the newer regions are the association cortex regions, which provide higher mental processing of
inputs such as shape, colour and size.
Sensory, motor and motivational (emotional or limbic) systems are organized both in parallel and in series
to produce a unified conscious experience. Each has
anatomically and functionally distinct subsystems that
30 SYSTEMS OF THE BODY
1
perform specialized tasks; for example, there are parallel
systems for touch, smell, taste and hearing, and within
each system, there are specialized subsystems for different aspects of the modality—sensation is broken down
into parallel pathways for pain, proprioception, posture
and balance. Motor systems likewise have parallel pathways, one to control voluntary fine movements, and others to control reflexes and body posture (see Chapter 9).
The most striking feature of these pathways is that they
are topographically organized so that there is a complete
spatial map of the periphery in the brain for each modality. A key feature of the map is that it is distorted, so
that, for example, regions that are important in sensory
discrimination have the largest cortical representation.
Another feature of the system is that there are interconnections between the different parallel streams.
An intuitive assumption based on the many different functions of the nervous system is that distinct brain
functions are localized to specific areas of the brain, and
indeed, this is true for many functions. Thus localized
focal brain lesions lead to discrete neurological deficits.
Other higher mental functions have a more widespread
distribution throughout the cortex. For example, there
is no one area that we can call primary pain cortex; different aspects of pain are processed in widely anatomically separated brain regions. Similarly, language ability
(comprehension, production and appreciation) is widely
separated across different lobes of the brain, and damage to focal regions may produce subtle deficits, whereas
widespread injury, as occurs in stroke, often causes
severe language deficits.
Thus knowing the names of the different parts of the
nervous system is just the beginning of understanding
how humans behave. It requires integration of the motivational, sensory and motor systems. Consider this the
next time you are hungry and you go out to buy food.
The decision to go to get food arises in the limbic system,
which then instructs the somatic motor system to enact,
causing you to walk to the shops and buy food. The processes of eating and tasting your favourite meal are provided by the sensory and motor systems. In addition,
this influences the ANS, which feeds back to the hypothalamus to tell the brain that the hunger has been satiated (via increases in blood glucose levels).
There are more than 1000 disorders of the nervous
system. Neurological disease and mental illness affect
millions of people worldwide and cost billions to treat.
The following chapters aim to shed light on how knowledge of the functional anatomy, physiology and pharmacology of the nervous system can be used to diagnose
and treat some of the more important nervous system
disorders.
ORGANIZATION OF THE NERVOUS SYSTEM
31THE NERVOUS SYSTEM
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ELEMENTS OF CELLULAR
AND MOLECULAR
NEUROSCIENCE
Chapter summary
1. The cellular components of the nervous system are neurons and glia.
Neurons are the main communicators while glial cells play roles in
support, immune surveillance and homeostasis.
2. The main components of a neuron are the soma, dendrites and axon.
They display the fundamental property of excitability. The presence
of an axon is the key characteristic that differentiates neurons from
glial cells.
3. Glia comprise astrocytes, microglia and oligodendrocytes.
Astrocytes provide structural support and play roles in trophism
and homeostasis; they are also involved in the formation of the
blood– brain barrier and the scar reaction of the nervous system to
injury. Microglia are key players in immune surveillance, control of
inflammatory responses in response to infection or trauma, and the
stabilisation of neural circuits during development. Oligodendrocytes
are specialised cells whose main role is the production of central
nervous system (CNS) myelin—a lipid- rich sheath that covers certain
axons. Schwann cells are the equivalent of oligodendrocytes in the
peripheral ner vous system (PNS).
2
4. The resting membrane potential (RMP) of neurons is determined
by the intrinsic permeability of cells to potassium, sodium and
chloride ions. A variety of stimuli can trigger changes in the
membrane potential via depolarisation or hyperpolarisation of
neurons. Summation of small amplitude depolarisations can reach
the threshold required to trigger a larger scale depolarisation—the
action potential. The potential propagates unidirectionally and
non-decrementally in axons. Action potentials are all- or- none events;
they are triggered, or not, in a neuron and their amplitude is always
the same. In myelinated axons the propagation is saltatory, between
the nodes of Ranvier in the myelin sheath, whereas in unmyelinated
axons propagation is passive via sequential opening and closing of
ion channels.
2
5. Neurons communicate through synapses, which are specialised zones
of communication between cells. Synapses comprise a presynaptic
component, a postsynaptic component and a synaptic cleft. The
presynaptic side contains vesicles filled with neurotransmitters.
Vesicles can release their content through an exocytosis process,
following local depolarisation.
6. Neurotransmitters of the CNS and PNS are endogenous compounds
that belong to a variety of families, for example, peptides,
amino acids and monoamines. In most cases neurotransmitters
are synthesised in the presynaptic terminal, through enzymatic
reactions. Following synthesis, the neurotransmitters are packaged
in vesicles. After release, the neurotransmitters can act on a variety
of receptors that are located presynaptically or postsynaptically.
Neurotransmitters can be taken back into the presynaptic terminal
through specialised transporters and they can be inactivated by
specific enzymes.
7. Neurotransmitter receptors can be divided into various classes.
The two main classes are ionotropic and metabotropic receptors.
Ionotropic receptors are multimeric ligand- gated ion channels that
control the flow of various cations and anions and the subsequent
change of excitability of neurons. Metabotropic receptors are G-
ELEMENTS OF CELLULAR AND MOLECULAR NEUROSCIENCE
protein coupled receptors; ligand binding leads to the activation of a
G- protein response and various changes in intracellular signalling.
34
Introduction
The central nervous system (CNS) and peripheral nervous system (PNS) contain two main cell types: neurons
and glia. A few other minor types of cell with specific
functions, such as the choroid epithelial cells, are present
in the brain, but these are described in other chapters.
Neurons
Neurons are the cells of the nervous system that receive signals, process them and transmit the appropriate response
either to another neuron or to an effector such as a secretory cell or a muscle. The number of neurons in the human
nervous system is estimated to be approximately 100 billion (1 × 1011). The signals may be received directly from
the environment, for example, light falling on the photoreceptor cells of the retina, in the form of chemicals released
from other neurons at specialised junctions between them
or as electrical signals directly transmitted through lowresistance gap junctions between adjacent neurons.
SYSTEMS OF THE BODY
Neurons have a variety of sizes and morphologies,
although they all have three elements:
1. A cell body (soma), which contains the nucleus and
other intracellular organelles concerned particularly
with protein synthesis, cellular housekeeping
functions that are essential for cell survival and
secretory processes. The large numbers of ribosomes,
particularly those associated with the rough
endoplasmic reticulum or polyribosomes, appear in
tissue specimens as darkly stained ‘Nissl bodies’. Cell
body diameter ranges from 5–120 μm.
2. Highly branched processes extending from the cell
body, called dendrites, which may be covered with
protrusions (spines, hence the term ‘spiny’ neurons);
cells without spines are called aspiny neurons. These
form the dendritic tree, which receives most of the
synaptic inputs from other cells.
3. A single axon extends from the cell body to the target
cell. Axons may extend just a few millimetres to a
nearby cell or, as in the case of the motor neurons
supplying muscles distant from the spinal cord, for
2
Dendritic spine
A
(trigger zone)
Synapse
Dendrites
Cell body
Nucleus
xon hillock
Axon
Schwann cell
(PNS)
Fig. 2.1 A typical multipolar neuron. CNS, Central nervous system;
PNS, peripheral nervous system.
(with nucleolus)
Oligodendrocyte
(CNS)
Node of Ranvier
Myelin sheath
several metres. The axon emerges from the soma at
the axon hillock. Close to the axon hillock is the axon
initial segment (also known as the trigger zone),
where electrical signals called action potentials are
generated. These are then propagated along the axon,
which terminates at a synapse. Axon diameter varies
from 0.2–20 μm.
The basic structure of a neuron is exemplified by the
typical multipolar neuron shown in Fig. 2.1.
The cytoskeleton of the neuron, like that of all cells,
consists of microtubules (composed of tubulin), microfilaments (made from actin) and intermediate filaments
called neurofilaments, which form the core of the axon.
Intracellular organelles, for example, mitochondria, are
generated in the cell body and are physically transported
along the axon by fast axonal transport along microtubules (anterograde transport) towards the axon terminal;
materials for recycling are returned in the same way in
the reverse direction (retrograde transport), using the
motor proteins kinesin and dynein. Slower axonal transport, which transports proteins to the synapse, may also
involve neurofilaments.
A single axon may give off occasional branches called
axon collaterals before reaching its target. At the end of
every axon there are a large number of branches, each
ending within a specialized structure called a synapse.
This is where signals are transmitted to other cells.
A typical synapse consists of a presynaptic terminal
and a postsynaptic region. Axons may contain swellings
along their length called varicosities, before forming the
presynaptic terminals, which are at the end of the axonal branches. These contain secretory vesicles and large
numbers of mitochondria. The presynaptic membrane is
slightly thickened and presents inward projections called
active zones. The postsynaptic region may also display
a zone of increased density. In some axons there are
synapses along the length of the axon without obvious
contact zones, which appear as swellings. These vesiculated axons are common in autonomic nervous system
(ANS) efferents. Both axons and dendrites are generically
called ‘neurites’, but can be distinguished by their morphology, their organelles and the organization of their
microtubules.
In general, neurons can be classified into one of three
major types, depending largely on the position and number of dendrites and the position of the trigger zone.
Most neurons are multipolar neurons, like the one
shown in Fig. 2.2A (and Fig. 2.1), and have many processes, which consist of one axon and many dendrites.
The trigger zone is close to the cell body. These are the
most common types of neurons and examples are the
pyramidal cells of the cortex and the Purkinje (see Fig.
2.2A) cells (PCs) of the cerebellum.
Bipolar neurons (see Fig. 2.2B) have a single axon and
a single dendrite, which only branches at its end. These
are relatively rare and are almost all found in special sensory organs. An example is the bipolar cells found in the
retina of the eye. The trigger zone is often found in the
same location as in multipolar neurons.
Pseudo- unipolar neurons (see Fig. 2.2C) have only
a single process extending from the cell body, which is
situated part of the way along the axon. This divides the
axon into central and peripheral processes. At the end
of the peripheral process lies a sensory ending, which
may be a bare axon, with the axon hillock and trigger
zone very close to the sensory ending. Pseudo- unipolar
neurons have no dendrites. The commonest pseudounipolar neurons are the sensory neurons found in the
PNS, which convey signals from the periphery to the
spinal cord in the CNS. Their cell bodies are found in
the spinal (dorsal root) or cranial nerve ganglion of the
PNS, and they synapse with neurons in the spinal cord
or brainstem.
Owing to their very active nature, neurons in general have a very high metabolic rate and they need a
continuous secure supply of oxygen and glucose. Any
interruption of this supply is critical, as oxygen- and
nutrient- deprived neurons will start to die very rapidly.
This is particularly problematic because, under most conditions, mature neurons do not divide. During development, epithelial cells lining the neural tube give rise to
neuroblasts. These cells divide mitotically to produce
amitotic neurons, which then migrate to their final positions in the brain. As this occurs during foetal development and is completed in early childhood, the mature
brain does not generally contain neurons that can divide.
Therefore, the implication is that lost neurons cannot be
replaced, not even in part. However, recent research has
ELEMENTS OF CELLULAR AND MOLECULAR NEUROSCIENCE
THE NERVOUS SYSTEM
35
2
ipheral process)
AB
Multipolar neurons Bipolar neuron Pseudo-unipolar neuron
Dendrites
Tr igger zone
Axon
Fig. 2.2 Neuron types. (A) Multipolar neurons—pyramidal cell (left) and Purkinje cell (right). (B) Bipolar neuron. (C) Pseudo- unipolar neuron.
Dendrite
Tr igger zone
Axon
C
Sensory
ending
Tr igger zone
Axon
(per
Axon
(central process)
ELEMENTS OF CELLULAR AND MOLECULAR NEUROSCIENCE
shown that some degree of neurogenesis (formation of
new neurons) continues in the adult brain (Box 2.1).
One result of the predominant non-mitotic characteristic of neurons is that brain tumours derived from
neurons are very rare and occur almost exclusively as
neuroblastomas in children. Most primary malignant
brain tumours (those derived from brain cells and not
caused by metastases from elsewhere in the body) are
gliomas, which are derived from glial cells (see below).
appearance (Fig. 2.3). They are distinguished from neurons by the lack of Nissl substance and the presence of
a specific structural protein—glial fibrillary acidic protein—which is a key component of glial filaments. The
abundance of these glial filaments is not consistent.
Astrocytes are very heterogenous; their functions and
morphology differ by their location, developmental stage
and subtype. Fibrous astrocytes contain large numbers of
filaments and long unbranched processes; they are found
in the white matter tracts of the brain. Protoplasmic
astrocytes are the most prevalent, have fewer filaments
Glial cells
The other main category of cell in the nervous system is
glial cells, of which there are several types. The term ‘glia’
derives from the German word for glue/putty, as proposed
by the German physician Rudolph Virchow in the 19th
century. These cells have several functions including structural and metabolic support, immune functions, electrical
insulation of axons and support of impulse conduction. In
the CNS astrocytes, oligodendrocytes and ependymal cells
form the macroglia and are derived from the ectoderm.
In contrast, microglia originate from the mesodermal/
myeloid tissue. In the PNS the macroglia include Schwann
cells, satellite cells of sympathetic and sensory ganglia, and
glia present in the enteric nervous system.
and very branched tertiary processes and are found
mainly in the grey matter in the proximity of synapses.
In the human brain, a single protoplasmic astrocyte has
within its domain as many as 2 million neuronal synapses. Astrocytes have a number of fine processes that
surround neurons, capillaries and the ependymal cells
lining the ventricles and the pia mater, forming the glial
membrane. These astrocytic end- feet do not touch the
capillaries, but release factors that induce blood–brain
barrier characteristics in the capillary endothelial cells
(see Chapter 12). Astrocytes are important in regulating
K+ levels in the extracellular medium around neurons,
and in providing a store of glycogen to neurons, in the
form of lactate, when required. Astrocytes surrounding
neurons play an important role in controlling the distribution of neurotransmitters released by the neurons.
Astrocytes
They do this in two ways: first, by restricting diffusion,
and second, by transporting neurotransmitters into the
In the CNS the most abundant glial cells are astrocytes
(also called astroglia), characterised by their star- like
astrocyte, where they can be metabolized or recycled.
Astrocytes can also produce neurotrophic factors, such
36 SYSTEMS OF THE BODY
2
Box
Neural stem cells
2.1
During the development of the nervous system, cells in
the neural tube become multipotent stem cells, which can
divide into all the different cells of the brain. The mammalian brain contains resident precursor cell populations that
contribute to neural development and persist into adulthood. These findings have led to the idea that activation of
endogenous precursors may promote tissue repair. There is
now clear evidence that neurogenesis and gliogenesis can
continue throughout life. This is particularly valuable concerning the human brain, which displays limited self- repair
after injury. Various terms are used to designate the cells
that can potentially support neural repair: ‘neural stem
cells’, ‘neural progenitor cells’ and ‘neural precursor cells
(NPCs)’. The first term defines cells that are multipotent
and have very high self- renewal potential. They can give
rise to a progeny which can differentiate into neuronal
and non-neuronal cells. The second term defines cells with
more limited self- renewal ability. Finally, the third term is
often used to collectively designate both neural stem cells
and neural progenitor cells. The brain contains distinct
populations of NPCs. These include the cells in the subventricular zone (SVZ) and hippocampal NPCs that generate
neurons and glia, as well as the more specialised oligodendrocyte precursor cells (OPCs) that generate oligodendrocytes throughout life.
In rodents, NPCs in the forebrain SVZ contribute to olfactory memory, while NPCs in the hippocampal dentate gyrus
contribute to spatial learning and memory. Agents have
been identified that can induce proliferation and differentiation of NPCs in vivo and can promote brain repair in
experimental models. One of the most exciting developments in neurobiology in the last 15 years, rewarded by the
Nobel prize in 2012 to John Gurdon and Shinya Yamanaka,
is the ability to reprogramme adult differentiated cells (e.g.
skin fibroblasts) into stem cells, through the technology of
inducible pluripotent stem cells (iPSCs), using specific combinations of transcription factors. These cells can then be
differentiated in vitro to produce various cell types, e.g.
astrocytes, oligodendrocytes or neurons. Therefore, it has
become possible to study the specific response of patientderived neurons to various stimuli, thus providing a basis
for a better understanding of physiopathology and also
supporting the development of personalized therapeutics.
as glial- derived neurotrophic factor (GDNF), essential for
the development and survival of dopaminergic neurons.
Astrocytes play a critical role in the formation and maintenance of synapses, the control of blood flow and the
regulation of blood–brain barrier function.
Astrocytes have recently been shown to play a potentially more active role in signalling. Gap junctions link
adjacent astrocytes, through which small molecules can
diffuse, thus forming a complex communication network. When stimulated by neurotransmitters they show
changes in intracellular levels of Ca2+ ions, which spread
between astrocytes as waves. Gap junctions also occur
between astrocytes and neurons, possibly modulating
the behaviour of the neurons by allowing the passage of
Ca2+ between them (termed gliotransmission). After an
injury, astrocytes can become activated and rapidly form
a barrier around the affected area to contain the toxic
processes triggered by injury. When persistent, this barrier becomes a glial scar, which prevents CNS regeneration (see Chapter 4 for further details).
The precursors of astrocytes are radial glial cells
which, during early development, span the cerebral cortex, forming a scaffolding for the migration of new nerve
cells to their destinations. In the adult brain they are
present as Müller cells of the retina or Bergmann cells in
the cerebellum, which perform the same repair functions
in these regions as activated CNS astrocytes.
Microglial cells
Microglial cells were first characterised by Rio Hortega
at the start of the 20th century. They are derived from
the yolk sac during embryonic development and rapidly colonise the brain, where they ultimately represent
10%–15% of cells. They are maintained throughout life,
through proliferation. These cells are relatively small
and characterised by a stellate morphology under resting conditions (Fig. 2.4A). During the development and
maturation of the CNS they release growth factors and
also act as macrophages, removing debris produced by
the programmed cell death which occurs on a large scale
at this time, and assisting in the processes of dendritic
pruning and synapse elimination, which refines neuronal circuits. In the adult they are normally relatively
inactive, playing a local surveillance role in tissue, somewhat like a community police officer on patrol. However,
in the presence of almost any type of injury or insult to
the nervous system (e.g. stroke, infection or traumatic
brain injury) they become activated. They multiply and
change their morphology into an amoeboid, globular
appearance (see Fig. 2.4B), move rapidly towards the
site of the problem and revert to the role of phagocytotic
macrophages; they change from friendly police officers
into the riot squad! In this activated state microglia can
adopt one of two major polarisation states: M1 or M2.
The M1 phenotype is related to release of inflammatory cytokines, such as tumour necrosis factor (TNF)- α,
interleukin (IL)- 1β and also reactive oxygen species,
whereas the M2 phenotype is anti-inflammatory, linked
to the release of cytokines such as interleukin (IL)- 10, and
also participates in tissue remodelling after injury. M2
microglia possibly support oligodendrocyte differentiation towards remyelination (see below). It must be noted
that this M1/M2 dichotomy is rather simplistic, and
some perceive it as unhelpful and somewhat misleading, as there is ample evidence that microglia can exist
in a variety of intermediate states between M1 and M2.
Genome- wide expression profiling will no doubt contribute to a more thorough characterization of the extreme
ELEMENTS OF CELLULAR AND MOLECULAR NEUROSCIENCE
37THE NERVOUS SYSTEM
2
Capillary
Astrocyte
Neuron
Ependymal
cell
A
Fig. 2.3 (A) Drawing of an astrocyte. (B) Astrocytes that have been injected with a fluorescent dye so that the processes can be clearly seen.
(From Young B, Heath JW. (2000) Wheater’s functional histology, fourth ed, by permission of Harcourt Publishers.)
ELEMENTS OF CELLULAR AND MOLECULAR NEUROSCIENCE
A
Fig. 2.4 Morphology of resting and activated microglia. (A) Ramified microglia exhibit highly branched processes with which they are in contact
with the surrounding microenvironment. (B) Activated microglia retract processes and become enlarged due to organelle build- up and increased
metabolic activity (from Lowe J. (2020). Stevens & Lowe’s Human Histology. Oxford: Elsevier Ltd.).
B
B
complexity of microglia in the future. In neurodegenerative diseases, such as Alzheimer’s disease or Parkinson’s
disease, the sustained state of activation of microglia
may become responsible for exacerbated synaptic loss.
Oligodendrocytes and Schwann cells
Oligodendrocytes and Schwann cells are involved in
electrically insulating axons in the CNS and PNS, respectively. They are large cells with few processes, which
38 SYSTEMS OF THE BODY
wrap around the axons forming multiple lipid bilayers, with their plasma membranes generating a myelin
sheath. Damage to these cell types leads to demyelinating diseases (Box 2.2). These membranes have a high
lipid/protein ratio, which makes them excellent insulators (see below). The myelination of nerve fibres is an
important process and the number of myelin whorls
around an axon is related to the conduction velocity of
that axon. Oligodendrocytes can myelinate more than one
axon and the cell body lies between them. Schwann cells