Neurology: Cells and neurophysiology

Cells of the nervous system I: neurones

There are two major classes of cells in the nervous system: the neuroglial cells and neurones, with the latter making up only 10– 20% of the whole population. The neurones are specialized for excitation and nerve impulse conduction, and communicate with each other by means of the synapse and so act as the structural and functional unit of the nervous system.

Neurones

The cell body (soma) is that part of the neurone containing the nucleus and surrounding cytoplasm. It is the focus of cellular metabolism, and houses most of the neurone’s intracellular organelles (mitochondria, Golgi apparatus and peroxisomes). It is typically associated with two types of neuronal processes: the axon and dendrites. Most neurones also contain basophilic staining, termed Nissl substance, which is composed of granular endoplasmic reticulum and ribosomes and is responsible for protein synthesis. This is located within the cell body and dendritic processes
but is absent from the axon hillock and axon itself, for reasons that are not clear. In addition, throughout the cell body and processes are neurofilaments which are important in maintaining the architecture or cytoskeleton of the neurone. Furthermore, two other fibrillary structures within the neurone are important in this respect: microtubules and microfilaments, structures that are also important for axoplasmic flow (see below) and axonal growth.

The dendrites are neuronal cell processes that taper from the soma outwards, branch profusely and are responsible for conveying information towards the soma from synapses on the dendritic tree (axodendritic synapses). Most neurones have many dendrites (multipolar neurones) and while some inputs synapse directly onto the dendrite, some do so via small dendritic spines or gemmules. Thus, the primary role of dendrites is to increase the surface area for synapse formation allowing integration of a large number of inputs that are relayed to the cell body.

In contrast, the axon, of which there is only one per neurone, conducts information away from the soma towards the nerve terminal and synapses. Although there is only one axon per neurone, it can branch to give several processes. This branching occurs close to the soma in the case of sensory neurones (pseudo-unipolar neurones), but more typically occurs close to the synaptic target of the axon. The axon originates from the soma at the axon hillock where the initial segment of the axon emerges. This is the most excitable part of a neurone because
of its high density of sodium channels, and so is the site of initiation of the action potential. All neurones are bounded by a lipid bilayer (cell membrane) within which proteins are located, some of which form ion channels; others form receptors to specific chemicals that are released by neurones and others act as ion pumps moving ions across the membrane against their electrochemical gradient, e.g. Na+–K+ exchange pump.
The axonal surface membrane is known as the axolemma and the cytoplasm contained within it, the axoplasm. The ion channels within the axolemma imbue the axon with its ability to conduct action potentials while the axoplasm contains neurofilaments, microtubules and mitochondria. These latter organelles are not only responsible for maintaining the ionic gradients necessary for action potential production, but also allow for the transport and recycling of proteins away from (and to a lesser extent towards) the soma to the nerve terminal. This axoplasmic flow or axonal transport is either slow ( 1 mm/day) or fast ( 100–400 mm/day) and is not only important in permitting normal neuronal/synaptic activity but may also be important for neuronal survival and development and as such may be abnormal in some neurodegenerative disorders such as motor neurone disease as well as disorders associated with abnormalities of certain proteins such as tau.

Many axons are surrounded by a layer of lipid, or myelin sheath, which acts as an electrical insulator. This myelin sheath alters the conducting properties of the axon, and allows for rapid action potential propagation without a loss of signal integrity. This is achieved by means of gaps, or nodes (of Ranvier), in the myelin sheath where the axolemma contains many ion channels (typically Na+ channels) which are directly exposed to the tissue fluid. The nodes of Ranvier are also those sites from which axonal branches originate, and these branches are termed axon collaterals. The myelin sheath encompasses the axon just beyond the initial segment and finishes just prior to its terminal
arborization. The myelin sheath is formed by Schwann cells in the PNS and by oligodendrocytes in the central nervous system (CNS), with many CNS axons being ensheathed by a single oligodendrocyte while in the PNS, one Schwann cell provides myelin for one internode.

Synapses

The synapse is the junction where a neurone meets another cell, which in the case of the CNS is another neurone. In the PNS the target can be muscle, glandular cells or other organs. The typical synapse in the nervous system is a chemical one, which is composed of a presynaptic nerve terminal (bouton or end-bulb), and a synaptic cleft, which physically separates the nerve terminal from the postsynaptic membrane and across which the chemical or neurotransmitter from the presynaptic terminal must diffuse. This synapse is typically between an axon of one neurone and the dendrite of another (axodendritic synapse) although synapses are found where the point of contact between the axon and the postsynaptic cell is either at the level of the cell body (axosomatic synapses) or, less frequently, the presynaptic nerve terminal (axoaxonic synapse). A few synapses within the CNS do not possess these features but are low-resistance junctions (gap junctions) and are termed electrical synapses. These synapses allow for rapid conduction of action potentials without any integration and as such tend to enable populations of cells to fire together or in synchrony. They may also be important in the coupling of activity across cortical areas which may be important in some of the synchronized responses seen in the brain in sleep-wakefulness.
The specific loss of neurones is seen in a number of neurological disorders.

Did you know?

The adult human brain contains 100 billion nerve cells.

Cells of the nervous system II: neuroglial cells

There are four main classes of neuroglial cells within the central nervous system (CNS): oligodendrocytes, astrocytes, microglia and ependymal cells, all of which have different functions. In contrast, in the peripheral nervous system (PNS), Schwann cells are the glial cells involved in myelination and facilitating axonal regeneration.

Astrocytes are small stellate cells that are found throughout the CNS and classified either morphologically or ontogenetically. They have many important functions within the CNS and are not simply passive support elements.

They form a structural and supporting framework for neuronal cells and capillaries by virtue of their cytoplasmic processes, which Cells of the nervous system II: neuroglial cells Cells and neurophysiology 35 end in close apposition not only to neurones but also to capillaries. In this respect they form the glia limitans – where the astrocytic foot processes cover the basal laminae around blood vessels and at the pia mater.
They maintain the integrity of the blood–brain barrier (BBB), by promoting the formation of high-resistance junctions between brain capillary endothelial cells.
They are capable of taking up, storing and releasing some neurotransmitters (e.g. glutamate, -aminobutyric acid [GABA]) and thus may be an important adjunct in chemical neurotransmission within the CNS.
They can remove and disperse excessive ion concentration in the extracellular fluid, especially K+.
They participate in neuronal guidance during development (see Chapter 1), and may be involved in the response to injury, and adult neurogenesis.
They may have a role in presenting antigen to the immune system in situations where the CNS and BBB are damaged.
The most common clinical disorder involving astrocytes is their abnormal proliferation in tumours called astrocytomas. These tumours produce effects by compressing adjacent CNS tissue and this presents as an evolving neurological deficit (with or without epileptic seizures) depending on its site of origin. In adults, the tumours most commonly arise in the white matter of the cerebral hemispheres.

Microglial cells are the macrophages of the brain, and are found throughout the white and grey matter of the CNS. They are phagocytic in nature and are important in mediating immune responses within the CNS. They have a role in inflammation seen in some neurodegenerative disorders of the CNS, such as Parkinson’s disease, where there is great interest in whether they can be both neurotrophic as well as neurotoxic.

Ependymal cells are important in facilitating the movement of cerebrospinal fluid (CSF) as well as interacting with astrocytes to form a barrier separating the ventricles and the CSF from the neuronal environment. They also line the central canal in the spinal cord (see Chapter 5). These ependymal cells are termed ependymocytes to distinguish them from those ependymal cells that are involved in the formation of CSF (the choroid plexus) and those that transport substances from the CSF to the blood (tanycytes).

Tumours of the ependyma (ependymomas or choroid plexus pap-illomas) occur either in the ventricles, where they tend to produce hydrocephalus, or in the spinal cord, where they cause local destruction of the neural structures.

Oligodendrocytes are responsible for the myelination of CNS neurones, and are therefore found in large numbers in the white matter. Each oligodendrocyte forms internodal myelin for 3–50 fibres and also surrounds many other fibres without forming myelin sheaths. In addition, they have a number of molecules associated with them that are inhibitory to axonal growth, and thus contribute to the failure of axonal regeneration in the CNS.

Clinical disorders of oligodendrocyte function cause central demyelination which is seen in a number of conditions including multiple sclerosis, while abnormal proliferation of oligodendrocytes produces a slow-growing tumour (an oligodendroglioma) which tends to present with epileptic seizures.

Schwann cells are found only in the PNS and are responsible for the myelination of peripheral nerves by a process that involves the wrapping of the cell around the axon. Thus, the final myelin sheath is composed of multiple layers of Schwann cell membrane in which the cytoplasm has been extruded. Unlike oligodendrocytes, one Schwann cell envelops one axon and provides myelin for one internode. In addition, Schwann cells are important in the regeneration of damaged peripheral axons, in contrast to the largely inhibitory functions of the central neuroglial cells.

A number of genetic and inflammatory neuropathies are associated with the loss of peripheral myelin (as opposed to the loss of axons), which results in peripheral nerve dysfunction (demyelinating neuropathies). In addition, benign tumours of Schwann cells can occur (schwannomas), especially in certain genetic conditions such as neurofibromatosis type I, where there is the loss of the tumour suppressor gene, neurofibromin.

These tumours are typically asymptomatic but if they arise in areas of limited space they can produce symptoms by compression of the neighbouring neural structures; e.g. at the cerebellopontine angle in the brainstem or spinal root.
Finally, there is a group of rare disorders, typically inherited, that cause a central abnormality of myelination, which together are called leucodystrophies.

Did you know?

Einstein’s genius has been attributed to the fact that he had a much larger than normal number of glial cells.

Ion channels

An ion channel is a protein macromolecule that spans a biological membrane and allows ions to pass from one side of the membrane to the other. The ions move in a direction determined by the electrochemical gradient across the membrane. In general, ions will tend to flow from an area of high concentration to one of low concentration. However, in the presence of a voltage gradient it is possible for there to be no ion flow even with unequal concentrations. The ion channel itself can be either open or closed. Opening can be achieved either by changing the voltage across the membrane (e.g. a depolarization or the arrival of an action potential) or by the binding of a chemical substance to a receptor in or near the channel.

The two types of channel are called voltage gated (or voltage sensitive) and chemically activated (or ligand gated) channels, respectively. However, this distinction is somewhat artificial as a number of voltage sensitive channels can be modulated by neurotransmitters as well as by Ca2+. Furthermore, some ion channels are not opened by voltage changes or chemical messengers but are directly opened by mechanical stretch or pressure (e.g. the somatosensory
and auditory receptors).

The most important property of ion channels is that they imbue the neurone with electrical excitability and while they are found in all parts of the neurone, and to a lesser extent in neuroglial cells, they are also seen in a host of non-neural cells.

All biological membranes, including the neuronal membrane, are composed of a lipid bilayer that has a high electrical resistance, i.e. ions will not readily flow through it. Therefore, in order for ions to move across a membrane, it is necessary to have either ‘pores’ (ion channels) in the lipid bilayer or ‘carriers’ that will collect the ions from one side of the membrane and carry them across to the other side where they are released. In neurones, the
rate of ion transfer necessary for signal transmission is too fast for any carrier system and so ion channels (or ‘pores’) are employed by neurones for the transfer of ions across the membrane.

The fundamental properties of an ion channel are as follows:

It is composed of a number of protein subunits that traverse the membrane and allow ions to cross from one side to the other – a transmembrane pore.
The channel so formed must be able to move from a closed to an open state and back, although intermediate steps may be required.
It must be able to open in response to specific stimuli. Most channels possess a sensor of voltage change and so open in response to a depolarizing voltage, i.e. one that moves the resting membrane potential from its resting value of approximately −70 to −80 mV to a less negative value.

In contrast, some channels, especially those found at synapses, are not opened by a voltage change but by a chemical, e.g. acetylcholine (ACh). These channels have a receptor for that chemical and binding to this receptor leads to channel opening. However, many channels possess both voltage and chemical sensors and the presence of an intracellular ion or secondary messenger molecule (e.g. cyclic adenosine monophosphate [cAMP]) leads to a modulation of the ion flow across the membrane that the voltage-dependent process has produced.

Activation of the voltage sensor or chemical receptor leads to the opening of a ‘gate’ within the channel which allows ions to flow through the channel. The channel is then closed by either a process of deactivation (which is simply the reversal of the opening of the gate) or inactivation which involves a second gate moving into the channel more slowly than the activation gate moves out, so that there is a time when there is no gate in the channel and ions can flow through it.

The flow of ions through the channel can be either selective or non-selective. If the channel is selective then it only allows certain ions through and it achieves this by means of a filter. The selectivity filter is based on energetic considerations (thermodynamically) and gives the channel its name, e.g. sodium channel. However, certain channels are non-selective in that they allow many different types of similarly charged ions through, e.g. ACh cation channel.

The overall description of an ion channel is in terms of a number of different physical measures. The net flow of ions through a channel is termed the current; while the conductance is defined as the reciprocal of resistance (current/voltage) and represents the ease with which the ions can pass through the membrane. Permeability,
on the other hand, is defined as the rate of transport of a substance or ion through the membrane for a given concentration difference.

There are many different types of ion channel and even within a single family of ion-specific channels there are multiple subtypes, e.g. there are at least five different types of potassium channels. The number and type of ion channel govern the response characteristics of the cell. In the case of neurones, this is expressed in terms of the rate of action potential generation and its response to synaptic inputs.

Clinical disorders of ion channels

A number of pharmacological agents work at the level of ion channels, including local anaesthetics and some antiepileptic drugs. However, in recent years a number of neurological disorders, primarily involving muscle, have been found to be caused by mutations in the sodium and chloride ion channels. These conditions include various forms of myotonia (delayed relaxation of skeletal muscle following voluntary contraction, i.e. an inability to let go of objects easily) and various forms of periodic paralyses in which patients develop a transient flaccid weakness which can be either partial or generalized.

Furthermore, certain forms of familial hemiplegic migraine and cerebellar dysfunction are associated with abnormalities in the Ca2+ channel, and some forms of epilepsy may be caused by a disorder of specific ion channels. In other disorders there is a redistribution or exposing of normally non-functioning ion channels. This commonly occurs next to the node of Ranvier as a result of central demyelination in multiple sclerosis and peripheral demyelination in the Guillain– Barré syndrome, and results in an impairment in action
potential propagation. Finally, in some conditions, antibodies are produced in the body (sometimes in response to a tumour) which react with voltage gated ion channels, producing disorders in the central nervous system (e.g. limbic encephalitis and anti-voltage gated potassium channels) as well as in the peripheral nervous system (Lambert–Eaton myasthenic syndrome and anti-voltage gated calcium channels).

Did you know?

The second-most dangerous vertebrate in the world is the puffer fish, which produces a toxin (colloquially known as zombie powder) that specifically binds to sodium channels (tetrotodoxin) and can kill a person in less than 24 hours.

Resting membrane and action potential

Resting membrane potential

In the resting state, the neuronal cell membrane is relatively impermeable to ions. This is important in the generation of the resting membrane potential.

The major intracellular ion is potassium, compared to sodium in the extracellular fluid, and so the natural flow of ions according to their concentration gradients is for K+ to leave the cell (or efflux) and for Na+ to enter (or influx). The movement of positive ions out of the cell leads to the generation of a negative membrane potential or hyperpolarization, while the converse is true for positive ion influx (a process of depolarization). However, the resting
membrane is relatively impermeable to Na+ ions while being relatively permeable to K+ ions. At rest therefore, K+ will tend to efflux from the cell down its concentration gradient, leaving excess negative charge behind, and this will continue until the chemical concentration gradient driving K+ out of the cell is exactly offset by the electrical potential difference generated by this efflux (the membrane potential) drawing K+ back into the cell.

The membrane potential at which this steady state is achieved is the equilibrium potential for K+ (EK+) and can be derived using the Nernst equation (see figure for details). In fact, the measured resting membrane potential in axons is slightly more positive than expected because there is some small permeability to Na+ of the membrane in the resting state. The small Na+ influx is countered by an adenosine triphosphate (ATP) dependent Na+–K+ exchange pump which is itself slightly electrogenic. This pump is essential in maintaining the ionic gradients, and is electrogenic by virtue of the fact that it pumps out three Na+ ions for every two K+ ions brought in. It makes only a small contribution to the level of the resting membrane potential.

Action potential generation

One of the fundamental features of the nervous system is its ability to generate and conduct electrical impulses. These can take the form of generator potentials, synaptic potentials and action potentials – the latter being defined as a single electrical impulse passing down an axon.

This action potential (nerve impulse or spike) is an all-or-nothing phenomenon, that is to say once the threshold stimulus intensity is reached an action potential will be generated. Therefore information in the nervous system is coded by frequency of firing rather than size of the action potential. The threshold stimulus intensity is defined as that value at which the net inward current (which is largely determined by Na+ ions) is just greater than the net outward current (which is largely carried by K+ ions), and is typically around −55 mV (critical firing threshold). This
occurs most readily in the region of the axon hillock where there is the highest density of Na+ channels, and is thus the site of action potential initiation in the neurone. However, if the threshold is not reached, the graded depolarization will not generate an action potential and the signal will not be propagated along the axon.

Sequence of events in the generation of an action potential

The depolarizing voltage activates the voltage sensitive Na+ channels in the neuronal membrane, which allows some Na+ ions to flow down their electrochemical gradient (increased Na+ conductance). This depolarizes the membrane still further, opening more Na+ channels in a positive feedback loop. When sufficient Na+ channels are opened to produce an inward current greater than that generated by the K+ efflux, there is rapid opening of all the
Na+ channels producing a large influx of Na+ which depolarizes the membrane towards the equilibrium potential for Na+ (approximately +55 mV). The spike of the action potential is therefore generated, but fails to reach the equilibrium potential for Na+ because of the persistent and increasing K+ efflux.
The falling phase of the action potential then follows as the voltage sensitive Na+ channels become inactivated. This inactivation is voltage dependent, in that it is in response to the depolarizing stimulus, but has slower kinetics than the activation process and so occurs later. During this falling phase, a voltage dependent K+ current becomes important as its activation by the depolarization of the membrane has even slower kinetics than sodium channel inactivation. This voltage activated K+ channel leads to a brief period of membrane hyperpolarization before it deactivates and the membrane potential is returned to the resting state.
Immediately after the spike of the action potential there is a refractory period when the neurone is either inexcitable (absolute refractory period) or only activated to submaximal responses by suprathreshold stimuli (relative refractory period). The absolute refractory period occurs at the time of maximal Na+ channel inactivation, while the relative refractory period occurs at a later time when most of the Na+ channels have returned to their resting state but the voltage activated K+ current is well developed. The refractory period has two important implications for action potential generation and conduction. First, action potentials can be conducted only in one direction, away from the site of its generation and, secondly, they can be generated only up to certain limiting
frequencies.

Did you know?

Nerves can conduct action potentials at velocities of up to 402 km (250 miles) per hour.

Neuromuscular junction (NMJ) and synapses

In 1897 Sherrington coined the term synapse to mean the junction of two neurones. Much of the early work on the synapse was carried out on the cholinergic neuromuscular junction (NMJ), although it appears that this chemical synapse is similar in its mode of action to those found in the central nervous system (CNS). The chemical synapse is the predominant synapse type found in the nervous system, but electrical synapses are found in certain sites, e.g. glial cells.

Neuromuscular transmission (a model for synaptic transmission)

The sequence of events at a chemical synapse is as follows:

The arrival of the action potential leads to the depolarization of the presynaptic terminal (labelled (1) on figure) with the opening of voltage-dependent Ca2+ channels in the active zones of the presynaptic terminal and subsequent Ca2+ influx (2) (this is the stage that represents the major delay in synaptic transmission).
The influx of Ca2+ leads to the phosphorylation and alteration of a number of presynaptic calcium-binding proteins (some of which are found in the vesicle membrane) which liberates the vesicle from its presynaptic actin network allowing it to bind to the presynaptic membrane (3). These proteins include various different soluble NSF attachment proteins (SNAPs) and SNAP receptors (SNAREs).
The fusion of the two hemichannels (presynaptic vesicle and presynaptic membrane) leads to the formation of a small pore that rapidly expands with the release of vesicular contents into the synaptic cleft. The vesicle membrane can then be recycled by endocytosis into the presynaptic terminal, either by a non-selective or more selective clathrin- and dynamin-mediated process.
More recently an alternative form of vesicle release has been described called ‘kiss and run’ exocytosis or flicker-fusion and this describes the formation of a transient fusion pore between the vesicle and the presynaptic membrane.
Most of the released neurotransmitter then diffuses across the synaptic cleft and binds to the postsynaptic receptor (4). Some transmitter molecules diffuse out of the synaptic cleft and are lost, while others are inactivated before they have time to bind to the postsynaptic membrane receptor. This inactivation is essential for
the synapse to function normally and, although enzymatic degradation of acetylcholine (ACh) is employed at the NMJ, other synapses use uptake mechanisms with the recycling of the transmitter into the presynaptic neurone.
The activation of the postsynaptic receptor leads to a change in the postsynaptic membrane potential. Each vesicle contains a certain amount or quantum of neurotransmitter, whose release generates a small postsynaptic potential change of a fixed size – the miniature end-plate potential (mepp). The release of transmitter from several vesicles leads to mepp summation and the generation of a larger depolarization or end-plate potential (epp) which, if
sufficiently large, will reach threshold for action potential generation in the postsynaptic muscle fibre (5).
This vesicle hypothesis has been criticized, because not all CNS synapses contain neurotransmitters in vesicles and because electrical synapses are found in some neural networks. However, it is clear that electrical and chemical synapses can coexist in the same neurones and also it is increasingly recognized that neurones may
communicate with each other through a range of non-synaptic mechanisms.

Disorders of neuromuscular transmission

A number of naturally occurring toxins can affect the NMJ.

Curare binds to the acetylcholine receptor (AChR) and prevents ACh from acting on it and so induces paralysis. This is exploited clinically in the use of curare derivatives for muscle paralysis in certain forms of surgery.
Botulinum toxin prevents the release of ACh presynaptically. In this case an exotoxin from the bacterium Clostridium botulinum binds to the presynaptic membrane of the ACh synapse and prevents the quantal release of ACh. The accidental ingestion of this toxin in cases of food poisoning produces paralysis and autonomic
failure. However, the toxin can be used therapeutically in small quantities by injecting it into muscles that are abnormally overactive in certain forms of focal dystonia – a condition in which a part of the body is held in a fixed abnormal posture by overactive muscular activity. It is also used in cosmetic surgery to get rid of wrinkles.
A number of neurological conditions affect the NMJ selectively. These include myasthenia gravis, Lambert–Eaton myasthenic syndrome (LEMS) and neuromyotonia or Isaac’s syndrome.
In neuromyotonia the patient complains of muscle cramps and stiffness as a result of continuous motor activity in the muscle. This is often caused by an antibody directed against the presynaptic voltage gated K+ channel, so the nerve terminal is always in a state of depolarization with transmitter release.
In LEMS there is an antibody directed against the presynaptic Ca2+ channel, so that on repeated activation of the synapse there is a steady increase in Ca2+ influx as the blocking antibody is competitively overcome by exogenous Ca2+. The patient complains of weakness, especially of the proximal muscles, which transiently improves on exercise.
Myasthenia gravis, on the other hand, is caused by an antibody against the AChR, and patients complain of weakness that increases with exercise (fatigability) involving the eyes, throat and limbs. This weakness is due to the number of AChRs being reduced and the ACh released presynaptically competes for the few available receptors. More recently, a second antibody has been recognized in myasthenia gravis in patients without antibodies to the
AChR. This antibody is directed to a muscle specific kinase (MUSK), although exactly how this causes the syndrome is not fully known.

Electrical synapses

Electrical transmission occurs at a small number of sites in the brain. The presence of fast conducting gap junctions promotes the rapid and widespread propagation of electrical activity and thus may be important in synchronizing some aspects of cortical function. However unlike chemical synapses, electrical synapses:

are not unidirectional in terms of transmission of electrical information;
do not contain a synaptic cleft;
do not allow for synaptic integration.
The abnormal absence of gap junctions in Schwann cells leads to one form of peripheral hereditary motor sensory neuropathy.

Did you know?

Eating the meat of curare poisoned animals is not dangerous, because the toxin is only poisonous when it gets into the
bloodstream.

Nerve conduction and synaptic integration

Nerve conduction

Action potential propagation is achieved by local current spread and is made possible by the large safety factor in the generation of an action potential as a consequence of the positive feedback of Na+ channel activation in the rising phase of the nerve impulse. However, the use of local current spread does set constraints, not only on the velocity of nerve conduction; it also influences the fidelity of the signal being conducted. The nervous system overcomes these difficulties by insulating nerve fibres above a given diameter with myelin, which is periodically interrupted by the nodes of Ranvier.

In unmyelinated axons an action potential at one site leads to depolarization of the membrane immediately in front and theoretically behind it, although the membrane at this site is in its refractory state and so the action potential is only conducted in one direction (see Chapter 15). The current preferentially passes across the membrane (because of the high internal resistance of the axoplasm) and is greatest at the site closest to the action potential. However, while nerve impulse conduction is feasible and accurate in unmyelinated axons, especially in the very small diameter fibres where the internal axoplasmic resistance is very high, it is nevertheless slow. Conduction velocity can therefore be increased by either increasing the axon diameter (of which the best example is the squid giant axon with a diameter of ∼1 mm) or insulating the axon using a high-resistance substance such as the lipid-rich myelin.
Conduction in myelinated fibres follows exactly the same sequence of events as in unmyelinated fibres, but with a crucial difference: the advancing action potential encounters a high-resistance low-capacitance structure in the form of a nerve fibre wrapped in myelin. The depolarizing current therefore passes along the axoplasm until it reaches a low-resistance node of Ranvier with its high density of Na+ channels and an action potential is generated at this site. The action potential therefore appears to be conducted down the fibre, from node to node – a process termed saltatory conduction. The advantage of myelination is that it allows for rapid conduction while minimizing the metabolic demands on the cell. It also increases the packing capacity of the nervous system, so that many fast-conducting fibres can be accommodated in smaller nerves. As a result most axons over a certain diameter (∼1 μm) are myelinated.
Disturbances in nerve conduction are clinically seen when there is a disruption of the myelin sheath, e.g. in the peripheral nervous system (PNS) in inflammatory demyelinating neuropathies such as the Guillain–Barré syndrome and in the central nervous system (CNS) with multiple sclerosis. In both conditions there is a loss of the myelin sheath, especially in the area adjacent to the node of Ranvier, which exposes other ion channels, as well as reducing the length of insulation along the axon. The result is that the propagated action potential has to depolarize a greater area of axolemma, part of which is not as excitable as the normal node of Ranvier because it contains fewer Na+ channels. This leads to slowing of the action potential propagation and, if the demyelination
is severe enough, actually leads to an attenuation of the propagated action potential to the point that it can no longer be conducted – so-called conduction block.

Synaptic integration

Each central neurone receives many hundreds of synapses and each input is integrated into a response by that neurone, a process that involves the summation of inputs from many different sites at any one time (spatial summation) as well as the summation of one or several inputs over time (temporal summation).

Presynaptic

The presynaptic nerve terminal usually contains one neurotransmitter, although the release of two or more transmitters at a single presynaptic terminal has been described – a process termed cotransmission. The amount of neurotransmitter released is dependent not only on the degree to which the presynaptic terminal is depolarized, but also the rate of neurotransmitter synthesis, the presence of inhibitory presynaptic autoreceptors and presynaptic inputs from other neurones in the form of axoaxonic synapses. These synapses are usually inhibitory
(presynaptic inhibition) and are more common in sensory pathways.

Postsynaptic

The released neurotransmitter acts on a specific protein or receptor in the postsynaptic membrane and in certain synapses on presynaptic autoreceptors . When this binding leads to an opening of ion channels with a cation influx in the postsynaptic process with depolarization, the synapse is said to be excitatory, while those ion channels that allow postsynaptic anion influx or cation efflux with hyperpolarization are termed inhibitory.

Excitatory postsynaptic potentials (EPSPs) are the depolarizations recorded in the postsynaptic cell to a given excitatory synaptic input. The depolarizations associated with the EPSPs can go on to induce action potentials if they are summated in either time or space. Spatial summation involves the integration by the postsynaptic
cell of several EPSPs at different synapses with the summed depolarization being sufficient to induce an action potential. Temporal summation, in contrast, involves the summation of inputs in time such that each successive EPSP depolarizes the membrane still further until the threshold for action potential generation is reached.
Inhibitory postsynaptic potentials (IPSPs) are hyperpolarizations of the postsynaptic membrane, usually as a result of an influx of Cl− and an efflux of K+ through their respective ion channels. IPSPs are very important in modulating the neurone’s response to excitatory synaptic inputs (see figure). Therefore inhibitory synapses tend to be found in strategically important sites on the neurone – the proximal dendrite and soma – so that they can have profound effects on the input from large parts of the dendritic tree. In addition, some neurones can inhibit their own output by the use of axon collaterals and a local inhibitory interneurone (feedback inhibition), e.g. motor neurones and Renshaw cells of the spinal cord.
More long-term modulations of synaptic transmission are discussed and in some disorders of the nervous system (e.g. epilepsy, multiple sclerosis) abnormal transmission of information may occur via non-synaptic mechanisms.

Did you know?

A single Purkinje cell in the cerebellum receives in excess of 200 000 synapses.

Neurotransmitters, receptors and their pathways

Neurotransmitters and synaptic function

The neurotransmitter released at a synapse interacts with a specific protein in the postsynaptic membrane, known as a receptor. At some synapses the neurotransmitter also binds to a presynaptic autoreceptor that regulates the amount of transmitter that is released.
Receptors are usually specific for a given neurotransmitter, although several different types of that receptor may exist. In some cases co-released neurotransmitters can either modulate the binding of another neurotransmitter to its receptor or act synergistically on a common single ion channel (e.g. the γ-aminobutyric acid [GABA]–benzodiazepine–barbiturate receptor).

Receptors for specific neurotransmitters are either coupled directly to ion channels (T1R on figure, e.g. acetylcholine receptors (AChR); or to a membrane enzyme (T2R). In these latter instances the binding of the neurotransmitter to the receptor either opens an ion channel via an intracellular enzyme cascade (e.g. cyclic adenosine monophosphate [cAMP] and G-proteins) or indirectly modulates the probability of other ion channels opening in response to voltage changes (neuromodulation). These receptors therefore mediate slower synaptic events, unlike those receptors directly coupled to ion channels that relay fast synaptic information.

The activated receptor can only return to its resting state once the neurotransmitter has been removed either by a process of enzymatic hydrolysis or uptake into the presynaptic nerve terminal or neighbouring glial cells. Even then there are often intermediate steps in the process of returning the receptor and its associated ion channel to the resting state. At some synapses the affinity and, ultimately, the number of receptors is dependent on the previous activity of the synapse. For example, at catecholaminergic synapses the receptors become less sensitive to the released transmitter when the synapse is very active – a process of desensitization and down-regulation. This process involves a decrease in the affinity of the receptor for the transmitter in the short term, which goes on in the long term to an actual decrease in the number of receptors. The converse is true with synapses that are rarely activated (super-sensitivity and up-regulation), and in this way synaptic activity is modulated by its ongoing activity.

In addition, at some synapses the activation of the postsynaptic receptor–ion channel complex can modulate the long-term activity of the synapse, either by affecting the presynaptic release of neurotransmitter or the postsynaptic receptor response – a process known as either long-term potentiation (LTP) or long-term depression (LTD) depending on the actual change in synaptic efficacy over time. Therefore the state, number and types of receptor for a specific neurotransmitter as well as the presence of receptors to other neurotransmitters are all
important in determining the extent of synaptic activity at any given synapse.

Diversity and anatomy of neurotransmitter pathways

The nervous system employs a large number of neurotransmitters, which can be divided into groups.

Excitatory amino acids

These represent the main excitatory neurotransmitters in the central nervous system (CNS) and are important at most synapses in maintaining ongoing synaptic activity. The main excitatory amino acid is glutamate, which acts at a number of receptors (which are defined by the agonists that activate them). The inotropic receptors consist of the N-methyl-D-aspartate (NMDA) and non-NMDA receptors, and the former receptor with its associated calcium channel may be important in the generation of LTP, excitotoxic cell death and possibly epilepsy.

A separate group of G-protein associated glutamate receptors, the metabotropic receptors, respond on activation by initiating a number of intracellular biochemical events that modulate synaptic transmission and neuronal activity. These receptors may underlie long-term depression in the hippocampus.

Inhibitory amino acids

The major CNS inhibitory neurotransmitters are GABA, which is present throughout the CNS, and glycine which is predominantly found in the spinal cord. Abnormalities of GABA neurones may underlie some forms of movement disorders as well as anxiety states and epilepsy. While mutations in the glycine receptor have now been linked to some forms of hyperexplexia – a condition in which there is an excessive startle response, such that any stimulus induces a stiffening of the body with collapse to the ground without any impairment of consciousness.

Monoamines

The monoaminergic systems of the CNS originate from small groups of neurones in the brainstem, which then project widely to all areas of the CNS. They are found at many other sites within the body, including the autonomic nervous system. In all locations they bind to a host of different receptors and thus can have complex actions including a role in depression, schizophrenia, cognition and movement control.

Acetylcholine

This neurotransmitter is widely distributed throughout the nervous system, including the neuromuscular junction and ANS. Therefore, many agents have been developed that target the different cholinergic synapses in the periphery and which are used routinely in surgical anaesthesia. Several disease processes can affect the peripherally located cholinergic synapses, while secondary abnormalities in the central cholinergic pathways may be important in dementia of the Alzheimer type and Parkinson’s disease.

Neuropeptides

These neurotransmitters, of which there are many different types, are found in all areas of the nervous system and are often co-released with other neurotransmitters. They can act as conventional neurotransmitters as well as having a role in neuromodulation (e.g. pain pathways).

Did you know?

John Eccles won the Nobel prize in 1963 for his work demonstrating that synapses could be inhibitory as well as excitatory.

Main CNS neurotransmitters and their function

Did you know?

Eating chocolate releases natural endorphins which dulls pain and may also explain why many believe that chocolate is addictive in the same way as people can become dependent on opioid drugs. If the opioid receptors are blocked, the craving and euphoric feelings for chocolate diminish.

Skeletal muscle structure

Skeletal muscle is responsible for converting the electrical impulse from a lower motor neurone that arrives at the neuromuscular junction (NMJ) into a mechanical force by means of contraction. The arrival of the action potential leads to the release of acetylcholine (ACh) which activates the nicotinic ACh receptor (AChR) in the postsynaptic muscle, which in turn leads to the depolarization of the muscle fibre. This produces a calcium influx into the muscle fibre which leads to muscle contraction.

Structure of skeletal muscle

Skeletal muscle is composed of groups of muscle fibres which are long, multinucleated cells. These fibres contain myofibrils, which in turn are made up of thick and thin filaments that overlap to some extent giving this type of muscle its striated appearance. The myofibrils are bounded by the sarcolemma, which invaginates between the myofibrils in the form of transverse or T-tubules. This structure is separate from the sarcoplasmic reticulum (SR), which envelops the myofibrils and is important as an intracellular store of Ca2+. The sarcolemma is a complex structure and abnormalities in its membrane components have recently been found to underlie some forms of inherited muscular dystrophies.
The thick filament is composed of myosin and lies at the centre of the sarcomere.

Myosin is composed of two heavy chains that are form by the light and heavy meromyosin proteins (LMM and HMM, respectively).
The HMM portion contains S1 and S2 subfragments.
The S1 fragment consists of two heads and associated with each of these heads are two light chains.
The light chain found at the tip of the S1 head is termed nonessential and is responsible for breaking down adenosine triphosphate (ATP) at the end of the power stroke of crossbridge formation.
The remaining essential light chain is attached at the point where the S1 head swings out towards the actin and is important in the process of myosin head movement.
By virtue of the properties of LMM, myosin filaments spontaneously pack together so that the S1 heads are on the outside towards the actin filaments. The S1 heads therefore form the major part of the crossbridge with the actin.

Thin filaments are composed of F-actin, tropomyosin and troponin. Troponin is itself composed of three subunits (troponin-I, -C and -T).

These three components of the troponin complex all subserve different functions but as a whole they regulate muscle contraction by holding the tropomyosin in position so that it physically blocks the S1 head of the myosin from binding to the actin.
The depolarization of the muscle leads to a calcium influx which then binds to troponin, producing a conformational change in the thin filament such that the tropomyosin shifts off the binding site for myosin on actin.
Thus, tropomyosin and troponin regulate muscle contraction by a process of stearic block. In some muscles in other animals, the regulation of the interaction between actin and myosin lies with the myosin associated light chains.
At the point of overlap of these two sets of filaments is found the triad structure of a T-tubule, linked to two terminal cisternae of SR by foot processes.

Disorders of structural proteins in skeletal muscle – the muscular dystrophies

There are many disorders, including:

Disorders of excitability through mutations in the ion channels.
Inflammation within the muscle.
Abnormalities in the structural proteins.

These latter conditions underlie many of the inherited muscular dystrophies, of which the best characterized are Duchenne’s and the limb girdle muscular dystrophies.
Duchenne’s muscular dystrophy (DMD) is an X-linked disorder in which there is a deletion of the gene coding for the structural protein dystrophin, with the milder form of the disease (Becker’s muscular dystrophy) having a reduced amount of this same protein. Patients with DMD typically present early in life with clumsiness and difficulty in walking, with an associated wasting of the proximal limb muscles and pseudohypertrophy of the calf muscles. As the disease progresses the patient becomes increasingly disabled, with the development of cardiac and other abnormalities which lead to death, typically in the third decade. Characteristically, these patients have a raised creatine kinase (a marker of muscle damage) as the muscles in these patients are prone to necrosis as a result of the absence of dystrophin. This protein lies beneath the sarcolemma of skeletal (as well as smooth and cardiac) muscle and provides stability and flexibility to the muscle membrane, such that when absent the membrane can be easily disrupted. This allows entry of large quantities of Ca2+, which precipitates necrosis by excessive activation of proteases.

The limb girdle muscular dystrophies (LGMD), in contrast, can present at any age with progressive weakness of the proximal limb muscles and a raised creatine kinase. The condition can be inherited in a number of different ways, and recently the autosomal recessive forms of this condition have been found to contain abnormalities in the dystrophin associated glycoproteins, adhalin and the sarcoglycan complex. These proteins link the intracellular
dystrophin with components of the extracellular matrix and so are important in maintaining the integrity of the sarcolemma.
There is also some evidence that in myasthenia gravis antibodies can also be found against some of these structural proteins such as the ryanodine receptor and titin.

Disorders with inflammation of skeletal muscle – the myositides

In a number of disorders there is selective inflammation in skeletal muscle, including:

inflammation for unknown reasons with a predominant T-cell infiltrate (polymyositis);
inflammation with a predominant B-cell mediated process (dermatomyositis) that can be paraneoplastic in nature;
a degenerative disorder that has a significant secondary inflammatory response (inclusion body myositis).

The former two conditions tend to respond to immunotherapy, while inclusion body myositis does not. In all cases the inflammation damages the muscle, causing weakness often with pain, and a raised serum creatine kinase.

Did you know?

The biggest single muscle in the human body is gluteus maximus (in the buttocks), while the smallest is the stapedius muscle, which is found in the ear, and the strongest are the masseters, which help you chew.

Skeletal muscle contraction

Summary of sequence of events in the contraction of muscle

The arrival of the action potential at the neuromuscular junction (NMJ) leads to an influx of Ca2+ and the release of vesicles containing acetylcholine (ACh).
ACh then binds to the nicotinic ACh receptor (AChR) on the muscle fibre leading to its depolarization.
Ca2+ is then released from the sarcoplasmic reticulum (SR) of the muscle.
Ca2+ release leads to the removal of the blocking calcium binding protein complex of tropomyosin and troponin from actin, the main component of the thin filament.
Removal of this stearic block allows myosin, the major component of the thick filaments, to bind to actin via a cross-bridge.
The fibres are then pulled past each other; the cross-bridge between the two fibres is broken at the end of this power stroke by the hydrolysis of adenosine triphosphate (ATP).
The cycle of cross-bridge formation and breakage can then be repeated and the muscle contracts in a ratchet-like fashion.

Sequence of events in the contraction of muscle

Stage 1

In the resting state the troponin complex holds the tropomyosin in such a position that it blocks myosin from binding to actin (stearic block).

Stage 2

The arrival of an action potential at the NMJ causes a postsynaptic action potential to be initiated, which is propagated down the specialized invagination of the muscle membrane known as the transverse tubule (T-tubule). This T-tubule conducts the action potential down into the muscle, so that all the muscle fibres can be activated. It lies adjacent to the terminal cisternae of the SR in a structure known as a triad, i.e. a T-tubule lies between two terminal cisternae of the SR (muscle equivalent of smooth endoplasmic reticulum) which contain high concentrations of Ca2+.

The T-tubules are linked to the SR by foot processes, which are part of a calcium ion channel. The arrival of the action potential at the triad leads to the release of Ca2+ from the terminal cisternae, by a process of mechanical coupling. The action potential opens a common Ca2+ ion channel between the T-tubule and SR, which then allows Ca2+ to influx down its electrochemical gradient towards the myofibrils. The Ca2+ then binds to the troponin complex and this leads to a rearrangement of the tropomyosin so that the myosin head can now bind to the actin, forming a crosslink
or cross-bridge.

Stage 3

Once the myosin has bound to the actin there is a delay before tension develops in the cross-bridge. The tension pulls and rotates the actin past the myosin and this causes the muscle to contract. The cross-bridge at the end of this power stroke detaches the myosin from actin with hydrolysis of ATP, a process that is also calcium dependent.

The whole cycle can then be repeated. The process of crossbridge formation with filament movement is called the sliding filament hypothesis of muscle contraction, as the two filaments slide past each other in a ratchet-like fashion as the cycle repeats. The Ca2+ released by the terminal cisternae of the SR, allowing the process of cross-bridge formation and breakage, is actively taken back up into this structure by a specific Ca2+ pump.

Disorders of muscle contraction

Diseases of the muscles, which disrupt their anatomy, will lead to weakness as a consequence of a disorganization of contractile proteins. However, there are some disorders in which there is a disruption of the contractile process itself and examples of this are the rare periodic paralyses and malignant hyperthermia/ hyperpyrexia. In this latter condition there is an abnormality in the ryanodine receptor which is part of the protein complex linking the T-tubule to the SR. This leads, under certain circumstances such as general anaesthesia, to sustained depolarization, contraction and necrosis of muscles resulting in an increase in body temperature and multiorgan dysfunction. In contrast, the periodic paralyses involve abnormalities in the ion channels that can lead to prolonged inexcitability of muscles, which thus become weak and paralysed. These are rare disorders and respiratory muscles are not involved; the paralysis can be provoked by a number of insults such as exercise or high carbohydrate meals.

It is also important to remember that disorders of muscle contraction occur as a consequence of abnormalities at the NMJ, as well as with some inborn errors of metabolism. These latter metabolic myopathies involve inherited defects in either carbohydrate or lipid metabolism, which lead to either episodic exercise-induced symptoms or chronic progressive weakness.

Did you know?

Rigor mortis is the stiffening of muscles after death and is caused by calcium leaking through the walls of the dead muscle fibres.