Synaptic transmission

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Synaptic transmission

General principles

The majority of synapses in the brain and spinal cord are chemical, meaning that the communication between nerve cells is mediated by a neurotransmitter substance. Electrical synapses are much less common and can be used to synchronize activity in a group of neurons.

Electrical synapses

Electrical synapses are also known as gap junctions and are direct points of contact between the cytoplasm of adjacent neurons (Greek: sunapsis, point of contact). This allows very rapid two-way communication and synchronization of electrical discharges.

A gap junction is composed of around 100 intercellular channels called connexons that are inserted into the plasma membranes of adjacent cells (Fig. 7.1). Each connexon is composed of a hexagonal array of proteins called connexins, surrounding an aqueous channel that is 2 nm wide. The pores in adjacent cell membranes are aligned to form a ‘tunnel’ between the two cells. These can be opened or closed by a conformational change in the constituent proteins, regulated by phosphorylation state.

image
Fig. 7.1 Electrical synapses.
(A) Gap junctions are points of direct communication between the cytoplasm of adjacent cells, formed by protein complexes called connexons; (B) Each connexon is composed of six connexin subunits, surrounding a central pore.

Gap junctions represent a low-resistance pathway that allows charged particles and small molecules to flow freely in either direction and couples the electrical activity of adjoining cells. Groups of cells linked by gap junctions form an electrical syncytium which can generate large, synchronized discharges. This happens in certain brain stem nuclei that control breathing and may contribute to the generation of abnormally synchronized discharges in some forms of epilepsy (Ch. 11).

Chemical synapses

Most central nervous system synapses are chemical. The general structure and arrangement is similar to that of the neuromuscular junction (see Ch. 4) and a great deal of information about central synapses has been derived from experiments at the point of contact between nerve and muscle.

General structure (Fig. 7.2)

At a chemical synapse the plasma membranes of the two nerve cells are in close proximity, separated by a narrow synaptic cleft. The axon terminal of the presynaptic neuron contains membrane-bound synaptic vesicles that are loaded with neurotransmitter; it also contains numerous mitochondria to provide energy for neurotransmission.

image
Fig. 7.2 General structure of a chemical synapse.
The arrangement is similar to that of the neuromuscular junction between nerve fibres and skeletal muscle.

Peptide transmitters are synthesized in the cell body and pre-loaded into vesicles which are delivered to the axon terminal by fast axonal transport (see Ch. 5). Other transmitters are synthesized within the axon terminal and are loaded into synaptic vesicles by transport pumps in the vesicle membrane. Some are synthesized within the vesicle itself.

Excitatory and inhibitory synapses (Fig. 7.3)

Synapses can be excitatory or inhibitory. If the presynaptic neuron releases an excitatory transmitter (most commonly glutamate) then the membrane of the postsynaptic cell will be depolarized. This is referred to as an excitatory post-synaptic potential (EPSP) and is typically associated with an inward sodium current. If the presynaptic neuron releases an inhibitory neurotransmitter (the most common of which is gamma-aminobutyric acid or GABA) then the postsynaptic membrane will be hyperpolarized (inhibited). This is an inhibitory postsynaptic potential (IPSP) and is often associated with an inward chloride current (or an outward potassium current). EPSPs and IPSPs are graded potentials of a few millivolts that only influence the local membrane and then rapidly decay (see Ch. 6).

image
Fig. 7.3 Excitatory and inhibitory synapses.
Most excitatory synapses in the central nervous system utilize glutamate as a neurotransmitter (or aspartate, which acts at the same receptors); the main inhibitory transmitter in the brain and spinal cord is gamma-aminobutyric acid (GABA).

Release of neurotransmitter (Fig. 7.4)

Once loaded with neurotransmitter, synaptic vesicles are docked at the presynaptic membrane awaiting release. Docking takes place at active zones. These consist of multi-protein complexes that tether the synaptic vesicle to the presynaptic membrane and contain high concentrations of voltage-gated calcium channels. This leads to brisk calcium influx in response to axon terminal depolarization, since the concentration of calcium is 10,000 times higher in the extracellular fluid. The focal rise in free calcium causes a number of synaptic vesicles to fuse with the presynaptic membrane, emptying their contents into the synaptic cleft by exocytosis.

image
Fig. 7.4 Neurotransmission.
(A) Neurotransmitter molecules are stored in the presynaptic element within membrane-bound synaptic vesicles; (B) Arrival of an action potential at the axon terminal triggers calcium influx via voltage-gated calcium channels which causes the vesicles to fuse with the presynaptic membrane and discharge their contents into the synaptic cleft; (C) The transmitter diffuses across the synaptic cleft and interacts with receptors on the postsynaptic membrane, leading to ion fluxes that will either inhibit or (as in this case) excite the postsynaptic neuron.

Release is said to be ‘packeted’ (or quantized) since the total amount of transmitter entering the synaptic cleft is a whole-number multiple of the amount stored in a single vesicle. Transmitter release is regulated by presynaptic autoreceptors which exert negative feedback.

Transmitter inactivation

To ensure that neurotransmission is a discrete event, the transmitter substance must be quickly removed from the synaptic cleft. In the case of acetylcholine this is achieved by enzymatic degradation (by acetylcholinesterase) but in most cases the transmitter molecule is reclaimed by the presynaptic neuron via membrane-bound reuptake proteins and recycled into new synaptic vesicles. Postsynaptic cells (and surrounding glia) also take up and metabolize neurotransmitters.

The entire process of synaptic transmission, from the arrival of the nerve impulse at the presynaptic element to the generation of a new nerve impulse in the postsynaptic cell, incurs a synaptic delay which may be up to five milliseconds. Chemical synapses are thus much slower than electrical synapses. However, each synaptic station in a neural pathway provides an opportunity for impulse traffic to be modulated or filtered.

Key points

image The majority of CNS synapses are chemical, meaning that communication is mediated by a neurotransmitter substance. This incurs a synaptic delay of up to five milliseconds.

image Electrical synapses (gap junctions) are much less common, but are faster and allow electrical synchronization of activity among groups of neurons.

image Chemical synapses can be excitatory or inhibitory. The most common excitatory transmitter in the CNS is glutamate, whilst the most common inhibitory transmitter is GABA.

image Transmitter is stored in synaptic vesicles which are ‘docked’ at active zones in the presynaptic membrane. Membrane fusion (and exocytosis) is triggered by a rise in intracellular calcium.

image Neurotransmitter diffuses across the synaptic cleft (between the presynaptic and postsynaptic cells) and interacts with specific receptors in the postsynaptic membrane.

image Transmitters are inactivated by enzymic destruction (e.g. in the case of acetylcholine) or by specific reuptake proteins on presynaptic cells, postsynaptic cells or perisynaptic glia.

Neurotransmitters

Approximately 50 to 100 substances are known (or suspected) to be neurotransmitters in the central nervous system. The reason that many of these chemicals are referred to as suspected or putative transmitters is that it is surprisingly difficult to prove that a substance is acting as a neurotransmitter, particularly in the human brain. This is because nervous tissue is densely packed with neurons, glial cells and blood vessels, surrounded by extracellular fluid in which there are numerous transmitters, peptides and hormones – and because synaptic events are fleeting and occur on a microscopic scale.

A number of criteria must be satisfied to establish that a substance is a neurotransmitter. It must be demonstrated that the candidate molecule: (i) is synthesized in the presynaptic neuron; (ii) is present within the axon terminal; and (iii) is released in a calcium-dependent manner upon depolarization of the presynaptic cell. It must also be shown that exogenous application of the substance has the same effect on the target cell as depolarizing the presynaptic cell. Relatively few molecules have satisfied these strict criteria unequivocally.

Classical neurotransmitters

Classical, small molecule neurotransmitters are stored in clear-cored vesicles that are approximately 50 nm in diameter. The first to be identified was acetylcholine (ACh) and it remains the best understood. Acetylcholine is found at the neuromuscular junction and throughout the autonomic nervous system. It differs from other types of neurotransmitter and has a distinct chemical structure, biosynthesis and mechanism of inactivation (Fig. 7.5). Acetylcholine is synthesized in axon terminals from two metabolites that are present in all cells: acetyl-coA and choline. This is achieved by the enzyme choline acetyltransferase (ChAT) which is only present in cholinergic neurons. The remaining small molecule neurotransmitters are divided into amino acids and biogenic amines.

image
Fig. 7.5 Acetylcholine synthesis, release and degradation.

Biogenic amines

This group of neurotransmitters includes noradrenaline (norepinephrine), adrenaline (epinephrine) and dopamine. These transmitters are produced from the amino acid tyrosine by decarboxylation (removal of the carboxylic acid group) leaving a single amino group (–NH2) to form a monoamine. They are classified as catecholamines due to the presence of a catechol ring, which is composed of six carbon atoms. The common biosynthetic pathway for the catecholamines is illustrated in Figure 7.7.

image
Fig. 7.7 Synthesis of catecholamines.

Inactivation of catecholamines is achieved via reuptake into axon terminals. After reuptake, the catecholamines face one of two fates: (i) recycling into new synaptic vesicles; or (ii) degradation by the enzymes catechol-O-methyltransferase (COMT) or monoamine oxidase (MAO).

Serotonin (5-hydroxytryptamine, 5-HT) is also a biogenic amine, but contains an indole group which has a bicyclic (or two-ring) structure rather than a single catechol ring. It is therefore classified as an indolamine. Serotonin is synthesized from the amino acid tryptophan and its pathway for biosynthesis and degradation is separate from that of the catecholamines (Fig. 7.8).

image
Fig. 7.8 Synthesis of serotonin.

Key Points

Other signalling molecules

A number of other molecules are present in the synaptic cleft and are often co-released with a classical transmitter. The most important of these are the neuropeptides and nitric oxide gas.

Neuropeptides

More than 40 neuromodulator peptides (varying from 3–40 amino acids in length) have been identified in the central nervous system. They are stored within large, dense-cored vesicles that are over 100 nm in diameter. Peptides have a longer-term, neuromodulatory effect on the target cell by interacting with metabotropic (G-protein-coupled) receptors (discussed below). Their actions are thus mediated by second messenger molecules and may lead to lasting changes in gene expression.

Three groups of neuromodulator peptides are part of the endogenous nociceptive (pain) and analgesic system of the brain: enkephalins, endorphins and dynorphins. The enkephalins (met-enkephalin and leu-enkephalin) have incredibly potent pain-relieving properties: more than 100 times stronger than morphine. The endorphins and dynorphins are referred to as opioid peptides because they share the same endogenous receptors with opiates such as morphine and heroin (diamorphine) and have similar effects including pain relief and euphoria.

Nitric oxide

A small number of gaseous molecules have been shown to act as central neurotransmitters. The best known is nitric oxide (NO) which is synthesized from the amino acid L-arginine by the enzyme nitric oxide synthase (NOS). Unlike small molecule transmitters and neuropeptides, nitric oxide is a volatile gas which cannot be stored in synaptic vesicles and must therefore be synthesized as required. Its action is relatively brief (less than ten seconds) since it is rapidly inactivated to form inert nitrates and nitrites.

Nitric oxide is unusual in other respects, including the ability to diffuse freely away from the point of origin, permeate cell membranes and influence neighbouring cells. Nitric oxide produced in a postsynaptic cell can therefore diffuse backwards across the synapse to the presynaptic element and act as a retrograde messenger (Latin: retro, backwards). The mechanism of action is by modulation of intracellular second messenger cascades, increasing the cytosolic concentration of cyclic GMP.

Key Points

Postsynaptic receptors

The majority of fast neurotransmission is mediated by glutamate and GABA, which act at a number of postsynaptic receptors. The effect on the target cell depends on the receptor expressed (or its subunit composition). For this reason, the same transmitter may excite one cell, but inhibit another.

Types of receptor

The process by which a transmitter alters the electrical properties of the postsynaptic cell is called transduction. It is mediated by postsynaptic receptors of two types: ionotropic and metabotropic.

Metabotropic receptors

These channels are linked to GTP-binding proteins (G-proteins) which influence the cell via effector proteins which may be ion channels, enzymes or elements within an intracellular cascade (Fig. 7.9). For instance, receptor binding may activate an enzyme that alters the phosphorylation state of the target: activation of kinases leads to phosphorylation (addition of phosphate group) whereas phosphatases have the opposite effect. If the target is an ion channel, alteration of the phosphorylation state may open or close it (Fig. 7.10). Alternatively, intracellular cascades may lead to changes in second messengers such as cyclic AMP (cAMP, the concentration of which is controlled by the enzyme adenylate cyclase) or cytosolic free calcium levels. In some cases there are long-term changes in gene expression caused by activation of nuclear transcription factors. Metabotropic receptors are therefore responsible for long-term neuromodulation rather than fast neurotransmission.

image
Fig. 7.9 Metabotropic (G-protein-coupled) receptors interact with second-messenger cascades in the neuronal cytoplasm, rather than directly opening or closing ion channels.
This can have complex and long-lasting effects on the cell, including changes in gene expression.
image
Fig. 7.10 Kinases and phosphatases may be used to regulate ion channels by adding and removing phosphate groups (P).

Glutamate receptors

Glutamate is synthesized and stored in perisynaptic glia and in the neuronal axon terminal. It acts both at ionotropic and metabotropic receptors, which can be assembled from an array of subunits (Fig. 7.11).

image
Fig. 7.11 Classification of glutamate receptors.
The figure shows the various subunits from which individual receptors of each type can be assembled, in various combinations. Ionotropic receptors are tetrameric, whereas metabotropic receptors form heterodimers. Most AMPA receptors incorporate the GluR2 subunit which makes them impermeable to calcium; those lacking the GluR2 subunit behave more like NMDA receptors and take part in learning, memory and excitotoxicity.

Ionotropic glutamate receptors

Three types of glutamate receptor are linked to ion channels. They are classified by their response to the exogenous ligand N-methyl-D-aspartate (NMDA) as NMDA and non-NMDA and each consist of a tetrameric assembly of subunits.

NMDA receptors and calcium

At the resting membrane potential the ion channels of NMDA receptors are inactivated by magnesium ions (Mg2+), as shown in Figure 7.12. Once the neuronal membrane has been depolarized and this magnesium block is lifted, sodium and calcium ions are able to enter the cell. NMDA receptors therefore have the unique property of being both ligand-gated and voltage-sensitive. Also, because of their high calcium permeability, they are able to effect long-term changes in neuronal biochemistry by initiating downstream, calcium-dependent events.

image
Fig. 7.12 NMDA glutamate receptors and calcium.
(A) NMDA receptors co-exist with non-NMDA (e.g. AMPA) receptors in the neuronal membrane; (B) Stimulation by glutamate opens AMPA receptors which depolarizes the cell by admitting sodium ions. NMDA receptors are also stimulated but the channel pore is occluded by magnesium ions; (C) With prolonged stimulation the magnesium block is lifted (as magnesium ions are repelled from the mouth of the channel pore by the increasingly positive interior face of the membrane). Once this has happened, calcium is able to enter the cell via the liberated NMDA channels.

Metabotropic glutamate receptors

Numerous G-protein-coupled glutamate receptors have been identified, many of which consist of a heterodimeric assembly of subunits (selected from mGLUR1-8; see Fig. 7.11). They fall into three main groups, but the majority are postsynaptic and excitatory. Some are presynaptic autoreceptors which help to regulate transmitter release at the synapse.

Memory and learning

The biological basis of memory is not fully understood, but one element appears to be that synaptic strength is able to increase or decrease, depending on usage: synaptic plasticity (Greek: plastikos, able to be moulded). A use-dependent increase in the efficacy of central synapses is termed long-term potentiation (LTP). An excitatory synapse that is used frequently is ‘potentiated’ (made stronger) by increased release of neurotransmitter from the presynaptic cell and increased sensitivity to transmitter in the postsynaptic cell (e.g. by inserting more receptors in the postsynaptic membrane). The presynaptic neuron is therefore more likely to depolarize the postsynaptic cell in future. Nitric oxide contributes to this process by acting as a retrograde messenger. Glutamate-mediated depolarization of the postsynaptic cell leads to an elevation of cytosolic calcium which trigger nitric oxide release. This then diffuses backwards across the synapse to influence the presynaptic element.

Associative phenomena

When a nerve cell is depolarized to threshold, any synapses that are active at the same time (and have contributed to the successful depolarization of the postsynaptic cell) may also be strengthened. This is referred to as an associative phenomenon (sometimes stated as ‘neurons that fire together, wire together’). Conversely, an incoming excitatory projection that is consistently active when the target neuron is not depolarized to threshold is progressively weakened (‘neurons that fire apart, fall apart’). Long-term weakening of a synapse, perhaps as a result of low or reduced levels of firing leads to long-term depression (LTD). This is important in the cerebellum during motor learning.

The mechanism of long-term potentiation, which depends upon controlled elevation of free cytosolic calcium, explains why glutamate is neurotoxic at high levels. Very strong glutamatergic stimulation leads to excessive calcium influx via NMDA receptors and GluR2-negative AMPA receptors, which damages the cell and may trigger programmed cell death. This process is termed excitotoxicity and is important in several nervous system disorders (see Ch. 8). Glutamate is therefore described as an excitotoxin when present at abnormally high concentrations.

GABA receptors

There are two types of GABA receptor: a fast (ionotropic) GABAA receptor that is mainly distributed within the limbic lobe, in areas that are concerned with emotion and memory; and a slow (metabotropic) GABAB receptor which is found throughout the cerebral hemispheres.

Ionotropic GABA receptors

The GABAA receptor is the target of several anti-anxiety drugs and its action is also modulated by alcohol (Clinical Box 7.1). It is a pentameric chloride ion channel assembled from more than a dozen varieties of alpha, beta, gamma and delta subunits. The reversal potential is around –65 mV, so that activation tends to maintain the hyperpolarized (inhibited) state of the cell.

image Clinical Box 7.1:   Anxiolytic drugs and alcohol

Many anxiolytic, sedative and hypnotic agents (used to treat anxiety or insomnia) act by stimulating GABAA receptors. These include: (i) benzodiazepines such as diazepam, which cause neuronal inhibition by increasing the frequency of chloride channel opening; and (ii) barbiturates such as phenobarbital, which increase the duration of channel opening by acting at a different binding site. One of the many effects of alcohol on the central nervous system is potentiation of GABAA receptors. Antagonism of the GABAA receptor (with agents such as picrotoxin) leads to convulsions, which is used in some animal models of epilepsy (Ch. 11).

Metabotropic GABA receptors

The GABAB receptor is widely distributed throughout the cerebral hemispheres. It is a heterodimeric G-protein-coupled receptor which leads to opening of potassium channels that hyperpolarize the cell membrane. Activation of GABAB receptors inhibits the cell for a longer period of time, but the effect is slower than at GABAA receptors.

Key Points

image Neurotransmitter receptors are of two major types: fast (ionotropic or ion-channel-linked) and slow (metabotropic or G-protein-coupled).

image The majority of fast excitatory neurotransmission in the CNS is mediated by glutamate (or aspartate) acting at ionotropic receptors. These are classified as NMDA and non-NMDA types.

image The non-NMDA receptors include the AMPA and kainate sub-types. NMDA receptors are calcium-permeable and are important for synaptic plasticity, memory and learning.

image An important cellular mechanism in synaptic plasticity is long-term potentiation (LTP), which describes a long-lasting (use-dependent) increase in synaptic efficacy or strength. NMDA glutamate receptors and nitric oxide are important contributors to LTP.

image The main inhibitory transmitter in the CNS is GABA. It acts at ionotropic GABAA receptors (present mainly in the limbic lobe) and the more widespread metabotropic GABAB receptors.

Synaptic integration

A typical neuron receives synaptic contacts from around 10,000 other cells. Many different transmitters are released and numerous cell-surface receptors are present to respond to these signals. The small excitatory and inhibitory postsynaptic potentials generated by activity in countless synaptic contacts are continuously integrated and summated. This determines the ‘firing rate’ of the cell and the frequency of nerve impulse generation from one moment to the next.

Spatial and temporal summation

The impact of a single excitatory postsynaptic potential on a target neuron is small, but if a number of convergent impulses from different nerve cells all reach the postsynaptic neuron together then the combined effect off these disparate influences may be sufficient to depolarize the cell to threshold and generate an action potential (Fig. 7.13). This is referred to as spatial summation.

image
Fig. 7.13 Spatial summation.
Excitatory projections from one or a small number of afferent fibres may be insufficient to cause depolarization in a target neuron (A), but it may be possible to trigger an action potential if several relatively weak impulses converge on the same target cell (B).

Similarly, although the influence of a single excitatory or inhibitory postsynaptic potential is small, the graded potential takes up to 15 milliseconds to decay – and may be additive if several nerve impulses arrive in rapid succession. This is referred to as temporal summation (Fig. 7.14) which operates together with spatial summation.

image
Fig. 7.14 Temporal summation.
A single, relatively weak excitatory postsynaptic potential (EPSP) may be insufficient to reach the threshold for generation of an action potential (A), but if several excitatory postsynaptic potentials arrive in quick succession (before the previous ones have completely decayed) then they may be additive and take the cell membrane to threshold (B).

The trigger zone for action potential generation is the initial segment of the axon. Summation of excitatory and inhibitory influences in this region of the membrane is critical for nerve impulse generation, so incoming synapses that are closer to this area stand a better chance of influencing neuronal firing rate than those at the distant reaches of the dendritic tree (Fig. 7.15).

image
Fig. 7.15 Different sites of synapse formation.
Since action potentials are triggered at the initial segment of the axon, synapses that are closer to this point (on the proximal dendrites or soma, rather than at the distant reaches of the dendritic tree) have a stronger influence on the target cell.

Some neurons exert a more powerful excitatory or inhibitory effect on their targets by making direct synaptic contact with the axon terminal. This is termed presynaptic facilitation or presynaptic inhibition, illustrated in Figure 7.16.

image
Fig. 7.16 Presynaptic facilitation (A) and inhibition (B).

Key Points

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