Synaptic transmission

Neurones interact with other neurones and with muscles. At the end of the axon of a neurone there is a widening called an end bulb (several in an axon terminal). There is a gap - usually called a synapse - between this and the next cell.

Big numbers!

The human brain consists of about 100 billion neurones and it has been estimated that each neurone forms 5000 to 10000 synapses, so the total number of synapses is between 5 x 10¹⁴ (500 trillion) and 10¹⁵ (1 quadrillion).

Types of synapse

A cholinergic synapse is one involving the neurotransmitter substance acetylcholine (ACh).
There are several other neurotransmitter substances but ACh is the most common.
ACh is mostly concerned with excitatory synapses, i.e. ones passing on impulses from neurone to neurone in the CNS and PNS, and also neuromuscular junctions.
Other (inhibitory) neurotransmitters may have the opposite action.

The main neurotransmitter

Acetylcholine is an ester formed between acetic (ethanoic) acid and choline - an alcohol with a quaternary ammonium cation section

Structure of a synapse

Events involved in transmission across a cholinergic synapse

As an impulse reaches the end of the axon, the action potential depolarises the membrane of the synaptic knob.

This causes (voltage-gated) calcium ion channels to open, allowing calcium ions to enter.

Calcium ions cause synaptic vesicles containing acetylcholine to move towards and then fuse with the (presynaptic) membrane.

Acetylcholine leaves the vesicles (exocytosis) and diffuses across the synaptic cleft.

ACh binds to (sodium channel) receptors on the postsynaptic membrane, which open.

As sodium ions enter, there is a depolarisation of the postsynaptic membrane.

Other synapses (nearby, on the same cell) can also contribute to the depolarisation, or oppose it - hyperpolarisation.

This postsynaptic potential is a graded potential which can result in the initiation (or not) of another impulse, leading onwards ...

Other neurotransmitter substances

There are many other neurotransmitter substances apart from acetylcholine. Some are specific to different parts of the body and parts of the brain. Each neurotransmitter has a different receptor, and a different transporter, and maybe causes different ions to move. There are also several versions (subtypes) of most of the receptors involved.

Under- or over-activity of some classes of neurotransmitters are responsible for some conditions, and a variety of medicinal drugs have been developed to control their activity.

Several neurotransmitters are amino acids and some are well known as components of proteins (proteinogenic). Some are known in other contexts, e.g. as hormones (adrenalin, epinephrine) or as part of inflammatory responses.

GABA - γ- (gamma-) amino butyric acid - is involved in many inhibitory synapses in the brain. GABA causes chloride ions Cl^- to enter postsynaptic neurones making them less able to transmit impulses (see below). Sedative drugs enhance the action of GABA.

Glycine is the corresponding inhibitory neurotransmitter in the spinal cord.

Glutamate is used at most excitatory synapses in the brain and spinal cord. It is thought to be especially involved in memory storage in the brain, and overactivity has been implicated in a number of conditions, including Alzheimer's disease, Huntington disease, and Parkinson's disease, as well as (ischemic) strokes and epilepsy.

A number of neurotransmitters are catecholamines, derived from the amino acid tyrosine:

Dopamine has a number of important functions in the brain; this includes regulation of motor behaviour, pleasures related to motivation and also emotional arousal, as well as playing a critical role in the reward system; Parkinson's disease has been linked to low levels of dopamine, and schizophrenia has been linked to high levels of dopamine
Endorphins are peptide hormones secreted by the brain especially the pituitary gland, produced in response to pain. Exercise, laughter and chilli heat can have a similar effect.
Endorphins bind to opioid receptors in presynaptic neurones and this causes the release of dopamine. These receptors are so called because compounds like morphine (and other opiates and opioids) also bind to them, causing analgesic (pain-killing) and sedative effects as well as providing pleasurable feelings of euphoria.

Norepinephrine (aka noradrenaline) and epinephrine (aka adrenaline) are also involved in mental alertness, as well as sleep patterns. So-called noradrenergic synapses are located in some sections of the brain, and norepinephrine is used as a neurotransmitter by sympathetic ganglia located near the spinal cord and in the abdomen.

Serotonin (5-hydroxy tryptamine, 5-HT) is a monoamine neurotransmitter, produced in the CNS but more generally in the intestine. It seems to regulate appetite, sleep, memory and learning, as well as operation of the body systems. Lower levels of serotonin may play a part in depression.

Histamine works within the central nervous system (CNS), notably the hypothalamus. It is involved with the control of arousal, learning, memory, sleep and energy balance.

Recycling

Acetylcholine is broken down by the enzyme (acetyl)choline esterase. This stops depolarisation.
The breakdown of acetylcholine
Acetic acid (ethanoic acid) can ionise to give acetate (ethanoate) CH₃COO^-
Choline diffuses into the synaptic cleft and is reabsorbed into the presynaptic knob. Here it is (re-)combined with an acetyl group and incorporated into vesicles, ready for use in a subsequent impulse.
Other neurotransmitters are not neutralised by hydrolysis, but they are quickly removed from the synapse and re-packaged into vesicles for re-use

There are specific protein transporter channels in the presynaptic membrane for the re-uptake of neurotransmitter components.

The production of vesicles, and the uptake of more acetylcholine, is a multi-stage energy-requiring process.

Calcium is actively pumped out of the presynaptic end bulb - similarly to the Na⁺/K⁺ pump which works along the axon.

Sodium is actively pumped out of the postsynaptic cell, restoring its resting potential.

There are a number of mitochondria in the end bulb and these obviously provide ATP for these energy-requiring processes.

Mitochondria can also provide acetyl Coenzyme A which donates the acetyl group for the (re-)formation of acetylcholine.

More about acetylcholine esterase

The enzyme acetylcholine esterase has a well-defined active site, often described as a gorge because of its distinctive shape. It has 2 main regions : the binding site - the 'anionic subsite', which holds the charged choline end of the substrate molecule - and beneath this is a catalytic active site - the 'esteratic subsite', which breaks the ester bond. The hydrolysis of acetylcholine is a very rapid process.

Acetylcholine esterase inhibitors

Other charged molecules can be attracted to the anionic subsite and not be affected by the esteratic subsite. This effectively blocks access to the active site and prevents the breakdown of acetylcholine.

As a result, postsynaptic membranes remain depolarised, nervous impulses may last longer or be stronger, and stimulated muscles remain contracted.

There are a number of symptoms resulting from the effects of acetylcholine esterase inhibitors on muscles of the body, summarised by the mnemonic SLUDGE.

Insecticides

Organophosphate compounds were found to be very toxic to insects as a result of their (irreversible) inhibition of acetylcholine esterase, the phosphate group occupying the anionic subsite where choline normally binds. There was thought to be a major difference in the toxicity of these compounds to mammals including Man and insects - in fact arthropods in general. Evidently this is a result of minor differences in the metabolism of these animal groups.

A number of these compounds have been marketed as insecticides, also used against arachnids. Malathion is the main one used for control of pest insects such as mosquitoes. Others have been replaced on the grounds of danger to human health. For example: dichlorvos - packaged as Vapona strip, which allowed evaporation of the volatile active ingredient - was considered very effective as a control method for insect pests in (limited) spaces such as shops and houses. However it was noted that people exposed continuously to it had lower levels of acetylcholine esterase in their blood plasma and often experienced a number of neurological symptoms. It was introduced as an insecticide in 1961 but banned in Europe in 1998. It is still available in some parts of the world.

Nerve agents (nerve gases)

As a consequence of research into organophosphate insecticides by German chemists in the 1930s, a number of compounds (Sarin and Tabun) were found to have effects on Man and these were seen as candidates for use in warfare, but they were not used in World War II. Other more toxic compounds (including 'VX' and various Novichok agents) have been discovered since then by researchers in the USA, UK and Russia. These compounds have regrettably been used in a number of scenarios since.

Medicinal applications

Several acetylcholine esterase inhibitors are used clinically.
Donepezil is a medication used in the palliative treatment of Alzheimer's disease. It is not a cure for Alzheimer’s disease, but it may help slow down the speed of progression of symptoms. There are also a number of possible systemic side effects.
Because there is often a lower concentration of acetylcholine in the brain of a person suffering from this condition, communication between neurones can be less efficient, resulting in memory loss and confusion.
As an acetylcholine esterase inhibitor, donepezil reduces the (natural) breakdown of acetylcholine, which means more is available to attach to receptors, so that more ACh is present and remains attached for longer. This results in a greater influx of sodium ions, so that depolarisation of the post-synaptic membrane is achieved, and an action potential is generated in the receiving neurone, leading to an impulse being propagated.

Neurotransmitter reuptake inhibitors

Other neurotransmitter substances may not be hydrolysed after an impulse has passed but simply removed from the synapse and passed back via the cell membrane into the presynaptic neurone from which they originated. This involves reuptake channels which may be inhibited by other compounds, leading to similar consequences to acetylcholine esterase inhibitors. This inhibition may be competitive, a result of molecular similarity with the neurotransmitter substance, or an allosteric effect, so that the reuptake inhibitor changes the shape of the recognition site for the neurotransmitter. In each case the neurotransmitter remains in place in the synapse for longer, increasing in concentration and has a greater effect.
For example, serotonin reuptake inhibitors (SRIs) are a class of drugs which block the action of the serotonin transporter (SERT), leading to increased extracellular concentrations of serotonin and an increase in 'serotonergic neurotransmission' in these cells. They may have an antidepressant effect.

Progress of nervous impulses

Unidirectionality

A nerve impulse in the presynaptic neurone can only generate an impulse in the postsynaptic neurone, so it travels in one direction only. This is because:

• only the presynaptic neurone has the vesicles containing the neurotransmitter
• only the postsynaptic neurone membrane has the receptors for the neurotransmitter.

Temporal and spatial summation

Sometimes a single impulse in the presynaptic neurone is not enough to cause a response from the postsynaptic neurone.

See the figures on the opposite side as you pass the mouse pointer over the following paragraphs
Tablet users: tap .. mobile users; tap show/hide

Synaptic interactions between neurones

Impulses from neurones P, Q and R may interact in several ways
- see figures alongside
Temporal summation .. Show / hide
and
Spatial summation .. Show / hide

Inhibition by inhibitory synapses

Inhibition .. Click to show / hide

Effects of specific drugs on synapses

Many medicinal drugs have their effect by enhancing or inhibiting the effects of neurotransmitters within the body, acting within the nervous system or on muscles or glands.

Other ('recreational' and 'psychedelic') drugs may also work by mimicking the action of neurotransmitters, or blocking receptors or reuptake mechanisms.

Neuroactive substances may be taken into the body by a number of means: via the digestive system, by injection into the blood or through mucous membranes lining the nasal passages (smoke and chemicals which are sniffed up). In all cases these substances are distributed via the blood to almost all parts of the body. There is a so-called blood-brain barrier which prevents certain substances (of higher molecular weight?) from entering the brain.

However these substances are likely to have much more gross effects than the (electro)chemical interactions caused by normal nerve activity, which is delivered via a specific and limited pathway (nerve fibres and synapses). At synapses neurotransmitters are normally removed by specific hydrolytic enzymes and/or transport mechanisms (reuptake channels etc). The amounts of the artificial substances taken in may far exceed the effective concentrations of normal biochemicals participating in the body's nervous interactions.

Introduced neuroactive substances may have a variety of effects on different parts of the body, and affect nervous as well as muscular tissue, including the heart, and blood vessels. They may have direct effects on the passage of individual nervous impulses or the pattern of nervous activity within sections of the brain , as well as affecting the clear-up processes after nerve impulses have passed.

Drugs generally have their effects as a result of similarities in their molecular shape with normal chemicals within the cells, perhaps by binding differently with normal cell components. In this way they may affect any of the stages in nervous activity: sodium and potassium ions channels in axon membranes, calcium ion channels and synaptic vesicles in pre-synaptic bulbs, receptors in post-synaptic membranes, or inhibiting hydrolytic enzymes and reuptake channels. Some chemicals (agonists) increase or potentiate nervous activity, others (antagonists) may inhibit it.

Not all the substances listed opposite are active at the synapse level, but I have put them together for interest. And I have included some information about acetylcholine esterase inhibitors and neurotransmitter reuptake inhibitors above, as well as neuromuscular inhibitors below, too.

Neuroactive compounds

None of the substances in the list below carries any recommendations from me (RGS).

I have seen some of my web pages blocked by certain networks merely as a result of mentioning drugs by name, so I am wary about including much detail about these. I may make a separate web page on this topic in the future. In the meantime, please let me know if you encounter any problems, or even any misgivings about including them here.

These compounds could be used as the basis for individual (internet-based?) research projects. Include details of source, mechanism of action, receptors affected etc.

Cocaine, also Novacaine (procaine) and Lidocaine (xylocaine, lignocaine)

LSD (lysergic acid diethylamide)

Psilocybin - active ingredient in magic mushrooms

Alcohol

Nicotine

Muscarine

Atropine - check out Atropa belladonna

Digitalis - source of Digoxin

Cannabis

Amphetamines

Ecstacy MCPA

Ketamine

Other substances - used to be called legal highs

Galantamine

Adrenaline

Tetrodotoxin

Strychnine

Ouabain

Physostigmine (also known as eserine)

Batrachotoxin

Aconitine

(sodium) Valproate and valproic acid (VPA)

Structure of a neuromuscular junction

When a nervous impulse from a motor neurone arrives at a muscle, the interaction has several similarities with a synapse.

Effects of specific drugs on neuromuscular junctions

Curare is an alkaloid plant extract from Central and South America, commonly known as an arrow poison (but not to be confused with poison arrow substances - batrachotoxins - derived from frogs: these act directly on sodium ion channels, so they interfere with the passage of nerve impulses).

This substance binds with the nicotinic acetylcholine receptor of some neuromuscular junctions.

It mainly affects skeletal muscle, not cardiac (heart) muscle.

As an arrow poison, it is used to kill prey animals in the forest canopy, even though the injury caused by the arrow itself may not be sufficient to kill. Death is caused by paralysis of respiratory muscles, especially the diaphragm, resulting in asphyxiation. The toxin is not likely to be poisonous to consumers of the resulting meat as it is not absorbed in the intestine.

Curare acts as a competitive antagonist - similar to a an enzyme inhibitor - of the (nAChR) acetylcholine receptor, preventing the normal action of acetylcholine.

Medically, curare has been used as a muscle relaxant in conjunction with anaesthetics during surgery.

Interestingly, curare poisoning may be treated by the administration of an acetylcholinesterase (AChE) inhibitor. This works by preventing the normal hydrolysis of acetylcholine, causing it to build up and compete with curare for the site on the receptors.

Botox, a toxic substance obtained from the bacterium Clostridium botulinum, causative organism of botulism food poisoning, also works on neuromuscular junctions.

It works by interfering with the fusion of vesicles with the presynaptic membrane, preventing the release of the neurotransmitter acetylcholine from axon endings, so that muscles are not stimulated by nervous impulses.

It is in fact the most acutely lethal toxin known. It has been used medically to treat conditions caused by overactive muscle movement, and cosmetically to treat frown lines.

Clostridium tetani, the causative organism of lockjaw - nowadays simply known as tetanus, is a related organism and its neurotoxin works similarly. However it results in a tight muscular contraction - spasm - rather than the loosening effect of botulinum toxin. The masseter muscle - the main chewing muscle of the jaw - is often the first muscle to be affected by the toxin when someone is infected by this anaerobic bacterium.

α-Neurotoxins in the venom of several species of snake antagonistically bind tightly and noncovalently to nicotinic ACh receptors (nAChRs) of skeletal muscles [see below], thereby blocking the action of ACh at the postsynaptic membrane, inhibiting ion flow and leading to paralysis.

β-Neurotoxins act against the presynaptic neurone, either preventing release of acetylcholine, or enhancing it.

Widow spider venom forms pores in the synaptic knob membrane, and causes the uncontrolled release of calcium ions into the presynaptic knob, causing uncontrolled release of acetylcholine and resulting in painful muscle contraction and paralysis.

Comparison of transmission across a cholinergic synapse and across a neuromuscular junction

Cholinergic synapses and neuromuscular junctions both use the neurotransmitter acetylcholine

Cholinergic synapses and neuromuscular junctions are both excitatory.
[Other neurone to neurone synapses may use other neurotransmitters and be inhibitory]

A synapse is a junction between two (different types of) neurones (e.g. sensory-intermediate, intermediate-motor).
A neuromuscular junction is a junction between the axon terminal of a motor neurone and a muscle.

Different muscle types (skeletal muscle and smooth/cardiac muscle) have different ACh receptors.

Nicotinic ACh receptors in skeletal muscle respond to the neurotransmitter acetylcholine, but they also respond to nicotine which selectively binds to the receptor, possibly reducing the effect of acetylcholine.
These are called ligand-gated ion channels, because they open when a specific molecule becomes attached: When ACh binds with them, the receptor molecules undergo a transformation in shape, opening a pore and allowing sodium ions to pass through the muscle cell membrane and enter the muscle cell in the area of the motor end plate which is beneath the presynaptic bulb. Potassium ions can also pass through the pores (in the opposite direction).

Muscarinic ACh receptors in smooth/cardiac muscle also respond to the neurotransmitter acetylcholine, but also to muscarine, a toxic alkaloid found in Amanita muscaria (the 'fly agaric') and other fungi.
These are called G protein-coupled receptors because they activate internal signal transduction pathways.