Neuromuscular System
to study and to manipulate the gene expression
responses of cells and cell groups, we have much more
powerful and sensitive assays to bring to bear on these
questions.
4.4 Inborn Influences: How Deelopment,
Eolution, and Ongoing Function are Integrated
The study of species differences has proven to be a
powerful method for learning about developmental
mechanisms in biology for well over a century. The
application of gene expression studies (together with
the other manipulative neurogenetic techniques de-
scribed above) toward the problem of inborn species
differences in behavior is likely to produce powerful
insights into the developmental pathways that make
different members of a species behaviorally similar. Of
equal importance will be the light such research sheds
on developmental pathways that make individuals in
one species all different from members of another
species in the same way.
Comparative work is also expected to provide
unique information on the mechanisms evolution uses
to change brains in order to change behavior. Such
mechanisms are likely to involve changes to both the
autonomous characteristics of cells and changes in
cellular interactions. Many of these changes may
depend not on changes to the structure of gene
products, but rather on changes in silent parts of
DNA sequences that influence the context and timing
of gene expression. Understanding how such changes
are accomplished evolutionarily may provide new
technologies for dealing with neural dysfunction
caused by injury and disease.
Finally, behaviors that show inborn species dif-
ferences typically also have individually distinctive
components that are malleable in the lifetimes of
individuals. Comparative work could produce major
insights into the ways that dynamic developmental
and functional processes within and between neural
cells integrate development and evolution with on-
going activity.
See also: Behavioral Genetics: Psychological Pers-
pectives; Behavioral Neuroscience; Developmental
Behavioral Genetics and Education; Memory: Genetic
Approaches; Memory in the Fly, Genetics of; Mental
Illness, Genetics of
Bibliography
Breakefield X O (ed.) 1979 Neurogenetics: Genetic Approaches
to the Nerous System. Elsevier, New York
Gerlai R 1996 Seminars in Neuroscience 8: 15361
Greenspan R J, Kyriacou C P (eds.) 1994 Flexibility and
Constraint in Behaioral Systems. Wiley, New York
Hall J C, Greenspan R J, Harris W A 1982 Genetic Neuro-
biology. MIT Press, Cambridge, MA
Kelner K, Benditt J (eds.) 1994 Genes and behavior: A special
report. Science 264: 1685739
Pfaff D W, Berrettini W H, Joh T H, Maxon S C (eds.) 2000
Genetic Influences on Neural and Behaioral Functions. CRC
Press, New York
Plomin R 1999 Nature 402: C25C29 , p. C25
Pulst S M (ed.) 2000 Neurogenetics. Oxford University Press,
Oxford, UK
Wahlster D 1999 Single gene influences on brain and behavior.
Annual Reiew of Psychology 50: 599624
Weiss P (ed.) 1950 Genetic Neurology. The University of Chicago
Press, Chicago
E. Balaban
Neuromuscular System
The neuromuscular system links the central nervous
system to the peripheral nervous system and is
composed of a neural circuit including motor neurons
in the spinal cord, sensory neurons in the dorsal root
ganglion, and skeletal muscle fibers (Fig. 1A). The
neuromuscular system is essential to movements of the
body, the control of posture and breathing. Electrical
impulses triggered from the motor neuron propagate
along the motor axon and result in the release of the
neurotransmitter, acetylcholine, from the motor nerve
terminal at the synaptic contact, called the neuro-
muscularjunction(Fig.1B,C).Acetylcholinemolecules
diffuse across a small gap and bind acetylcholine
receptors on the muscle fiber. The binding results in
the opening of ion channels, thereby changing the
muscle membrane potential. The membrane depolari-
zation triggers a release of internal calcium ions that
leads to a cascade of events resulting in muscle
contraction (Fig. 1D). The muscle spindles and Golgi
tendon organs are sensory organs in the skeletal
muscle that detect changes in the muscle fiber length
and tension (Fig. 1E). The information is conveyed by
electrical impulses propagating along sensory fibers of
dorsal root ganglion neurons, which, in turn, innervate
motor neurons in the spinal cord. The activation of
motor neurons generates electrical impulses pro-
pagating along the motor axon and thereby com-
pleting the circuit of the knee-jerk reflex in the
neuromuscular system (Fig. 1A). Motor neurons in the
spinal cord also receive synaptic inputs from the brain
to perform voluntary movements.
1. The Neuromuscular Junction (NMJ)
The NMJ (Fig. 1B) plays an indispensable role in
transmitting information from the motor neuron to
the skeletal muscle (Salpeter 1987). The NMJ, also
called the endplate, is a specialized region on the
muscle surface, on which the motor nerve terminal
10595
Neuromuscular System

Sensory
neuron

Extensor
motor neuron
(activated)

Flexor
motor neuron
(inhibited)

Perisynaptic
Schwann cell

Sarcoplasmic Transverse
reticulum tubules

Figure 1
Schematic representation of the neuromuscular system (AE). (A) The circuitry of the neuromuscular system
involves motor neurons in the spinal cord, skeletal muscle, sensory receptors, and sensory neurons. Stretching of the
extensor muscle activates the muscle spindle and generates electric impulses in the sensory neuron, which, in turn,
excites the motor neuron that innervates the extensor muscle, causing muscle contraction. The sensory neuron acts
indirectly, through the inhibitory neuron, to inhibit the motor neuron that innervates the flexor muscle. Thus, the
knee-jerk reflex involves a coordinated contraction of the extensor muscle and relaxation of the flexor muscle.
(B) A light microscopic representation of the neuromuscular junction where an axon innervates a single muscle
fiber. (C) An electron microscopic representation of a cross-section of the neuromuscular junction. (D) An electron
microscopic representation of a longitudinal section of a segment of a single muscle fiber. (E) A diagram of a
muscle spindle showing intrafusal muscle fibers innervated by afferent and efferent axons

10596

makes a synaptic contact with a gap of approximately
50 nm, called the synaptic cleft (Fig. 1C), between these
two cellular elements. Besides the nerve terminal and
the muscle fiber, the third cellular element at the NMJ
are glial cells, called perisynaptic Schwann cells (also
known as terminal Schwann cells, Fig. 1C), which cap
the nerve terminal. At the adult vertebrate NMJ, each
skeletal muscle fiber is, in general, innervated by a
single motor axon. Due to its relative simplicity and
accessibility, the NMJ has served as a model system
for investigating the structure, function, and devel-
opment of chemical synapses (Sanes and Lichtman
1999).
1.1 The Motor Nere Terminal
Although the motor axon is wrapped by myelin sheath
formed by Schwann cells, the terminal region is only
capped by perisynaptic Schwann cells without myelin
formation (Fig. 1B). In mammalian muscles, the nerve
terminal branches into multiple grape-like varicosities,
called synaptic boutons, which occupy a circumscribed
region, approximately 50 m in diameter, or less than
0.1 percent of the muscle surface area. At the frog
NMJ, in contrast, the end of the motor fiber branches
out into several elongated branches, each of which can
extend several hundred m long. The diameter of
individual boutons or terminal branches is approxi-
mately 12 m. Electron microscopy reveals mito-
chondria and conspicuous synaptic vesicles (Fig. 1C),
approximately 2050 nm in diameter, inside the nerve
terminal. Synaptic vesicles tend to cluster around a
thickened membrane specialization called the active
zone (Fig. 1C) on the side of the nerve terminal facing
the muscle fiber. The active zone is believed to be the
site of transmitter release where the opening of
synaptic vesicles during intense stimulation can be
observed with electron microscopy (Heuser and Reese
1977). Freeze-fracture electron microscopy shows that
the active zone is composed of two double-rows of
large intramembrane particles ("10 nm in diameter),
located precisely opposed to the opening of junctional
folds where acetylcholine receptors are clustered on
the muscle surface (Fig. 1C). These large intra-
membrane particles are thought to correspond to the
location of voltage-gated calcium channels that allow
Ca#+ entry to trigger exocytosis of synaptic vesicles
and release of the transmitter. The precise alignment
of voltage-gated calcium channels at the active zone
and acetylcholine receptors at the junctional fold plays
a strategic role in the speedy action of the transmitter-
receptor interaction. The length of the active zone
correlates with the efficacy of synaptic transmission.
1.2 Transmitter Release
The neurotransmitter, acetylcholine, is stored in syn-
aptic vesicles. There are about 10' synaptic vesicles
Neuromuscular System
inside the nerve terminal at the frog NMJ. A variety of
proteins on the synaptic vesicle and on the nerve
terminal membrane govern the process of transmitter
release. Following nerve stimulation, the conductance
of voltage-gated calcium channels increases and the
intracellular calcium concentration rises transiently. It
is believed that some synaptic vesicle proteins serve as
Ca#+ sensors and trigger the exocytosis of synaptic
vesicles. Exocytosis involves binding between some
integral proteins in the vesicle membrane, called v-
SNARES, and some in the nerve terminal membrane,
called t-SNARES (Sudhof 1995). Their binding results
in fusion between the synaptic vesicle membrane and
the nerve terminal membrane at the active zone. Some
of these SNARES are the targets of neurotoxins. For
example, botulinum toxins cleave t-SNARES, causing
transmitter release blockade and muscle paralysis.
The transmitter can be released spontaneously or
evoked by nerve stimulation (Katz 1966). The spon-
taneous exocytosis of synaptic vesicles produces mini-
ature endplate potentials (mepps), which occur ran-
domly with an average frequency of about 1 Hz and
amplitude of 0.5 mV. It is believed that the mepp is
caused by the release of approximately 10,000 acetyl-
choline molecules stored in one synaptic vesicle. The
nerve stimulation evokes nearly synchronous release
of many synaptic vesicles and produces endplate
potentials (epps). The amplitude of epps is dependent
on Ca#+ influx in a non-linear manner such that a two-
fold increase in Ca#+ influx can increase the evoked
transmitter release up to 16-fold. In a normal saline
solution, each nerve impulse can trigger a synchronous
release of about 200 synaptic vesicles and result in an
epp that is large enough to trigger an action potential
and muscle contraction. Following transmitter release,
synaptic vesicle membranes are retrieved through a
process called endocytosis that involves membrane
invagination and formation of an endosome, a mem-
brane compartment inside the nerve terminal (Heuser
and Reese 1977). New synaptic vesicles bud off the
endosome, refilled with acetylcholine. The local re-
cycling of synaptic vesicles takes about 30 sec to 1
min to complete and provides the nerve terminal with
a continual supply of synaptic vesicles even under
intense stimulation.
1.3 Acetylcholine Receptors at the NMJ
The acetylcholine receptors (Unwin 1993) in skeletal
muscles belong to the nicotinic type because nicotine
derived from the tobacco plant activates these recep-
tors. This is in contrast to the muscarinic type of
acetylcholine receptors found in the brain that are
activated by muscarine derived from a poisonous red
mushroom. Both mepps and epps are caused by the
binding of acetylcholine to nicotinic acetylcholine
receptors on the muscle fiber. The acetylcholine
receptors are densely packed, approximately 10,000
per m#, at the endplate region, compared with fewer
10597
Neuromuscular System
than 10 per m# on the rest of the muscle membrane.
Each acetylcholine receptor at the adult NMJ consists
of five subunits: two -subunits, one -, one -, and sprouting after nerve injury (Son et al. 1996). Schwann
one -subunit. All of these five subunits contribute to
form the receptor channel. As a consequence of two
molecules of acetylcholine binding to the -subunits,
the receptor channel opens and allows ion flow that
results in depolarization of the muscle membrane.
Prior to innervation, acetylcholine receptors are
distributed throughout the muscle membrane at a
density of approximately 1000 per m# during de-
velopment. A protein, called agrin, triggers the ag-
gregation of acetylcholine receptors at the developing
NMJ (McMahan 1990). Agrin is synthesized by the
motor neuron, released from the motor nerve terminal,
and incorporated into the extracellular matrix (see
Section 1.5) in the synaptic cleft. Agrin interacts with
several molecules, including dystroglycan and a
muscle-specific tyrosine kinase, located on the muscle
membrane, and stimulates the aggregation of acetyl-
choline receptors, which are also associated with a
cytoplasmic protein termed rapsyn. Motor neurons
also enhance the synthesis of acetylcholine receptors
through a molecule named neuregulin, which interacts
with a set of receptor tyrosine kinases in the muscle
membrane (Fischbach and Rosen 1997). After nerve
injury, the density of acetylcholine receptors in the
muscle membrane outside the NMJ increases mark-
edly, a phenomenon termed denervation super-
sensitivity. Direct muscle stimulation can prevent or
reverse denervation supersensitivity. Thus, the motor
nerve plays a role not only in the aggregation and
synthesis of acetylcholine receptors, mediated by agrin
and neuregulin, respectively, but also in the nerve
activity-mediated suppression of acetylcholine recep-
tor expression in the extrajunctional region of the
muscle (Sanes and Lichtman 1999). As a result of these
effects of the motor nerve terminal, acetylcholine
receptors are concentrated at the endplate region
where they can readily bind acetylcholine molecules
released from the terminal.
1.4 The Perisynaptic Schwann Cell (PSC)
The PSC is a glial cell that overlays the nerve terminal
(Fig. 1C). The role of the PSC had not been studied
extensively until the 1990s. Neural activity can
cause an elevation of internal Ca#+ concentration and
regulate gene expression in the PSC. Conversely,
activation of the PSC can regulate the amount of
transmitter released. Thus, modulation of the efficacy
of neuromuscular transmission likely involves recipro-
cal interactions between the nerve terminal and the
PSC. Complex neuron-glia interactions have also been
found at the NMJ after nerve injury. PSC processes
sprout profusely beyond the original endplate region
following nerve injury. As reinnervation progresses,
nerve terminals closely follow the preceding PSC
10598
sprouts. It is believed that these PSC sprouts play a
role in guiding and leading nerve regeneration and
cells express many trophic factors that may be im-
portant for neuronal survival and axonal growth.
Thus, it is likely that the PSC plays a role in the
modulation of synaptic function, as well as in the
formation and maintenance of synaptic connections.
1.5 The Extracellular Matrix at the NMJ
Besides agrin, there are many important molecules
that reside in the synaptic cleft, which is filled with
amorphous material called the extracellular matrix or
basal lamina (Fig. 1C). Some of these molecules are
large glycoproteins, such as laminins, which may
promote nerve growth, adhesion between nerve and
muscle, or differentiation of the nerve terminal (Sanes
and Lichtman 1999). An important enzyme located in
the extracellular matrix is acetylcholinesterase, which
hydrolyzes acetylcholine molecules that do not bind to
acetylcholine receptors. The prompt removal of
acetylcholine from the synaptic cleft by acetyl-
cholinesterase prevents desensitization of acetyl-
choline receptors caused by the continuous presence of
acetylcholine. Thus, acetylcholinesterase plays an es-
sential role in ensuring proper transmission between
nerve and muscle (Salpeter 1987).
2. Skeletal Muscle Contraction
A typical mammalian skeletal muscle is composed of
hundreds of individual muscle fibers that are approxi-
mately 50100 m in diameter and 26 cm in length.
Each muscle fiber is a multi-nucleated muscle cell and
is made up of myofibrils, the contractile elements that
carry out the work of contraction. Each myofibril
consists of a chain of repeated contractile units called
sarcomeres (Fig. 1D). In each sarcomere, thin and thick
filaments run parallel to one another with varying
degrees of overlap depending on the contractile state.
The thin filament is made primarily of actin molecules
and the thick filament of myosin molecules. According
to the sliding filament model, Ca#+ triggers interactions
between actin and myosin molecules and results in the
sliding of thin and thick filaments past one another,
thereby causing muscle contraction. Following nerve
stimulation and synaptic transmission, electrical im-
pulses generated in the muscle fiber spread rapidly into
membrane invaginations, called transverse tubules,
which extend into sarcomeres and form contacts with
sarcoplasmic reticulum, a modified endoplasmic reti-
culum that sequesters and releases Ca#+. It is thought
that depolarization of the transverse tubule results in
the opening of Ca#+ release channels located on the
sarcoplasmic reticulum membrane. As a result, Ca#+ is
released from the sarcoplasmic reticulum into the

cytosol and initiates muscle contraction. Muscle relax-
ation occurs when Ca#+ ions are pumped back into the
sarcoplasmic reticulum. Thus, Ca#+ plays important
roles not only in transmitter release but also in
excitation-contraction coupling in the neuromuscular
system (Engel and Franzini-Armstrong 1994).
3. Sensory and Motor Controls of the
Neuromuscular System
The neuromuscular system is under both voluntary
controls and reflex controls. The motor neurons in the
spinal cord receive synaptic connections from other
neurons in the central nervous system for voluntary
control of body movements. The spinal motor neurons
are also involved in reflex controls to maintain proper
posture and to prevent muscle injury from excessive
contraction. Two sensory receptors, the muscle spindle
and the Golgi tendon organ, provide information on
muscle length and tension, respectively, to motor
neurons for reflex controls (Engel and Franzini-
Armstrong 1994). The message may excite or inhibit
motor neurons depending on the extent of the stretch
or the tension, and on the type of muscle involved.
Muscle spindles are embedded in, and run parallel
to the long axis of, the skeletal muscle (Fig. 1E). These
spindle-shaped sensory organs consist of a group of
intrafusal muscle fibers, which are modified muscle
fibers lacking myofibrils in the central region. Thus,
the centers of the intrafusal fibers are not contractile,
in contrast to the regular skeletal muscle fibers, which
are also called the extrafusal fibers. The ends of the
intrafusal fibers are innervated by nerve terminals of
small-diameter motor neurons, called motor neu-
rons. This is in contrast to the regular extrafusal fibers,
which are innervated by the large motor neurons.
Activation of motor neurons causes shortening of
the polar regions of the intrafusal fiber and thus
enhances the sensitivity of the muscle spindle to
stretch. In addition to motor innervation, intrafusal
fibers are also wrapped by nerve endings of sensory
(afferent) fibers. The cell bodies of sensory fibers reside
in the dorsal root ganglion.
The role of the muscle spindle is exemplified in the
knee-jerk reflex (Kandel et al. 2000). When the
quadriceps (extensor) muscle in the thigh is stretched,
for example, by tapping the kneecap with a small
rubber hammer, the stretching activates the sensory
nerve endings in the muscle spindle. This stimulation
generates receptor potentials and activates the sensory
neuron, which propagates electrical impulses towards
the spinal cord. The sensory axon makes excitatory
synapses directly onto the motor neuron that
innervates the extrafusal fibers of the quadriceps
muscle (Fig. 1A). Thus, the stretch of the muscle spindle
in the quadriceps muscle activates the motor neuron,
which, in turn, causes the quadriceps to contract. As a
result, the lower leg swings forward. This simple reflex,
Neuromuscular System
which involves only one synapse between the sensory
neuron and the motor neuron, is called the mono-
synaptic stretch reflex. In addition to the mono-
synaptic pathway, the sensory neuron acts indirectly,
through an inhibitory neuron, to inhibit the motor
neuron that innervates the opposing hamstring
(flexor) muscle (Fig. 1A). The knee-jerk reflex involves
a simultaneous activation of both pathways and
results in a coordinated contraction of the extensor
quadriceps muscle and relaxation of the flexor ham-
string muscle.
Whereas muscle spindles are most sensitive to
stretch, Golgi tendon organs are most sensitive to
tension. Golgi tendon organs reside at the junction
between the tendons and muscle fibers, and are thus
arranged in series to the skeletal muscle. Each tendon
organ, about 1 mm long and 0.1 mm in diameter,
consists of unmyelinated nerve endings that intertwine
among collagen fibers encapsulated by connective
tissue. Excessive muscle contraction activates Golgi
tendon organs, which inhibit motor neurons that
innervate the activated muscle. Thus, the Golgi tendon
organ provides negative-feedback control, which pre-
vents extreme muscle contraction that might damage
the muscle fibers.
4. Toxins that Affect the Neuromuscular System
Because of the importance of the neuromuscular
system to vital functions, such as respiration and
escape from predators, it is not surprising that nature
has evolved animals and plants that produce a variety
of poisons to block neuromuscular transmission and
thereby paralyze their prey. For example, -
bungarotoxin, a peptide found in the venom of the
banded krait Bungarus multicinctus, blocks neuro-
muscular transmission by irreversibly binding to
nicotinic acetylcholine receptors (Chang 1979). Be-
cause of its irreversible binding, -bungarotoxin has
been a useful tool to study the function and dis-
tribution of acetylcholine receptors at the NMJ.
Another acetylcholine receptor blocker is curare, a
mixture of plant toxins used for poison darts by South
American Indians. Other toxins block neuromuscular
transmission by affecting transmitter release. For
example, fish-hunting marine cone snails disable their
prey by injecting an array of toxins, known as
conotoxins, some of which block voltage-gated cal-
cium channels (Olivera et al. 1994). The venom in the
female black widow spider contains -latrotoxin that
causes a massive release of acetylcholine at the NMJ.
Botulinum toxin and tetanus toxin from bacterial
growth in infected food or tissues cleave some proteins
associated with synaptic vesicle release and thus
disrupt neuromuscular function. Another mode of
interfering with neuromuscular transmission is to
inactivate acetylcholinesterase. For example, many
deadly nerve gases are inhibitors of acetyl-
10599
Neuromuscular System
cholinesterase and cause paralysis of the respiratory
muscle through the accumulation of acetylcholine
molecules, thereby desensitizing and inactivating
acetylcholine receptors.
5. Diseases of the Neuromuscular System
Diseases of the neuromuscular system (Engel and
Franzini-Armstrong 1994) include disorders of the
NMJ, degeneration of motor neurons in the spinal
cord, and muscular dystrophies. The most common
disorder affecting transmission at the NMJ is my-
asthenia gravis. This disease is characterized by weak-
ness of limb muscles and cranial muscles. Myasthenia
gravis is an autoimmune disease in which patients
produce antibodies against their own nicotinic acetyl-
choline receptors at the NMJ. These antibodies inhibit
neuromuscular function by reducing the number of
functional receptors, or by interfering with the binding
of acetylcholine to the receptors. Another neuro-
muscular disorder is the Lambert-Eaton myasthenia
syndrome, also an autoimmune disease in which
patients generate antibodies against voltage-gated
calcium channels at the motor nerve terminal, thereby
disrupting transmitter release. The best-known motor
neuron disorder is amyotrophic lateral sclerosis, also
known as Lou Gehrig disease. It is not known why
only motor neurons, but not sensory neurons, die in
this devastating disease. As a result of the motor
neuron degeneration, patients experience weakness of
the arms and legs, and eventually suffer fatal failure of
respiratory muscles. Muscular dystrophies, charac-
terized by muscle weakness and loss of muscle fibers,
are myopathic diseases. One severe form of these
diseases is Duchenne muscular dystrophy, which is an
X-linked inherited disease causing symptoms only in
boys. The disease is attributed to a deficiency in
dystrophin, a large protein located on the inner surface
of the muscle membrane. Dystrophin links actin
molecules and an array of glycoproteins that form a
complex near the muscle membrane. Absence of
dystrophin or some of these dystrophin-associated
glycoproteins causes a disruption of the muscle mem-
brane and thereby muscle degeneration.
See also: Classical Mechanics and Motor Control;
Motor Control; Motor Control Models: Learning and
Performance; Neural Plasticity of Spinal Reflexes;
Somatosensation; Synapse Formation; Synapse Ultra-
structure; Synaptic Transmission
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McMahan U J 1990 The agrin hypothesis. Cold Spring Harbor
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Salpeter M M 1987 The Vertebrate Neuromuscular Junction.
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C.-P. Ko
Neurons and Dendrites: Integration of
Information
1. Introduction and Scope
At the beginning of the twenty-first century, neural
tissue remains arguably the most powerful substrate
for information processing in existence. Unfortu-
nately, the principles underlying brain function are
still known only in rough outline. To unlock the many
secrets of the brain, and to help explain the panoply
of neural functions ranging from simple motor reflexes
to conscious thought and action, neuroscientists have
amassed an extensive body of experimental data
bearing on the properties of nerve cells (neurons) and
their interconnections (synapses), which together form
the building blocks of neural tissue. At the same time,
the functional significance of the neurobiological data
has been explored in computer modeling studies,
which have often been used to test hypotheses inac-
cessible to direct experimental approaches. This article
summarizes what is known about the intracellular
physiology of individual nerve cells, and interprets
these data in relation to the information processing
ISBN: 0-08-043076-7