Synaptic Transmission

Question 1

The neurone:

Answer 1

Human nervous system contains more than 10 billion neurons
Basic structure includes:
cell body (perikaryon). -Nucleus. -Schwann cell/oliogodendrocyte
-terminal (synaptic). -axon hillock. -dendrite. -axon. node of ranvier

Question 2

Classification of neurones:

Answer 2

unipolar neurones: its a single process from cell body, sensory neurones (information from body to brain/spinal cord)

bipolar neurones: one dendrite and one axon from cell body; retina, internal ear, olfactory mucosa (nose)

multipolar neurones: several dendrites and one axon from cell body; most neurones in brain and spinal cord are like this also motor neurone (information from brain/spinal cord to body.)

Question 3

Functional classifications:

Answer 3

peripheral NS neurones:
*afferent neurones carry impulses to the CNS carrying information about internal and external environment
*efferent neurones carry impulses from the CNS to effectors
central NS neurones:
*interneurones carry nerve impulses from 1 neurone to another within the CNS, form circuits for processing information

Question 4

The CNS:

Answer 4

Cerebrum: the back of the brain
Pons and medulla: together make up the brain stem. The brain stem tissue is continuous with the spinal cord, which continues down the spine

Question 5

The PNS (periphery):

Answer 5

-12 pairs cranial nerves. Spinal nerves made up of :
-cervical (neck)
-thoracic (thorax)
-lumbar (small of back)
-sacral (below small of back)
-coccygeal (one pair of last. Vertebracoccyx)

Question 6

Subdivisions of the PNS:

Answer 6

-Somatic-voluntary, conscious, : afferent from sense receptors (e.g.temperature,pain touch) and special sense receptors (e.g. smell, sound, taste) to CNS, motor- efferent- from CNS to skeletal muscle.
- Autonomic- involuntary, automatic; sensory afferent from visceral sense receptors (e.g. co2) to CNS. Motor- efferent from CNS to smooth muscle, cardiac muscle, glands etc. divided into parasympathetic and sympathetic systems.

Question 7

The synapse:

Answer 7

for an electrical signal to pass from 1 neurone to another it must cross a synapse;
Maybe chemical e.g. between 2 neurones, or between a neurone and a muscle fibre etc.
Or electrical; tubular structures. Called connexons form gap junctions- electrical synapses do exist (rarely) in the NS but are more likely to be encountered between cardiac and smooth muscle cells

Question 8

Synaptic delay:

Answer 8

-A short (milliseconds) delay occurs between arrival of the action potential at the axon terminal and generation of the action potential in the post-synaptic cell.
-when many synapses are involved in a complex reflex response, delay at each synapse is cumulative.
-the quickest response which can be obtained is from a monosynaptic reflex e.g.knee jerk reflex

Question 9

How is a chemical transmitter is produced?

Answer 9

By a presynaptic neurone and is released by action potential. This action potential first depolarises the axon terminal allowing the transmitter to be released into the synaptic cleft

-The transmitter diffuses a short distance to bind on the post synaptic membrane. As the transmitter binds it causes a graded depolarisation. If the depolarisation exceeds the threshold an action potential is developed in the post synaptic neurone

Question 10

Comparison between electrical and chemical synapses

Answer 10

-Action potentials reaching an electrical synapse will always be transmitted to the next cell
-An action potential reaching at a chemical synapse may not release enough transmitters to allow the postsynaptic cell to fire an action potential
-The transmitter can be depleted when there is intense stimulation of the synapse when there is intense stimulation of the synapse. Excitability will be restored if time is allowed to replenish the transmitter
-The post synaptic cell may have reduced sensitivity to excitation which would reduce its probability of firing an action potential
-The same transmitter may be excitatory at some synapses and inhibitory at others, depending on the type of receptors located on the post synaptic membrane.
-Chemical transmission occurs in only one direction, from the pre to the post-synaptic membrane.

Question 11

Motor units:

Answer 11

1 axon and the muscle fibres it innervates
In fine movement, e.g. eye muscles, 1 axon innervates only a few muscle fibres
For gross movements, e.g. postural muscles, 1 axon may innervate hundreds of fibres
The axon terminal comes close to the skeletal muscle, but does not touch it, there is a gap, the synaptic cleft between the nerve and muscle

Question 12

Most studied synapse: The NMJ

Answer 12

Neuromuscular junction is a specialised synapse- the synapse between a motor neurone and a skeletal muscle fibre
Transmitter always Ach receptor all nicotinic
Features include:
-Motor neurone fibre and terminal
-Neuromuscular cleft (synaptic cleft)
-Folded sarcolemma (muscle fibre membrane)
-Area of sarcolemma known as motor end plate

Question 13

Where is acetylcholine produced?

Answer 13

Acetylcholine is synthesised from choline and acetyl co-enzyme A by choline acetyltransferase in the cytoplasm of the axon terminal

Choline + acetyl co enzyme A ——-> Acetylcholine
Choline acetyltransferase

-Release of very small amounts of arch at the n-m junction but this is not enough to generate an action potential in sacrolemma
-Following stimulation when an action potential reaches the axon terminal, about 20 vesicles releases their arch this is enough to open 50000 ion channels in the end plate.

Question 14

What happens to released acetylcholine?

Answer 14

When Ach diffuses to the post-synaptic membrane it binds to the nicotinic receptor for an instant . In order to allow the cell to recover and respond to a new stimulus, the Ach must be rapidly removed from the junction

Some Ach will diffuse away from the junction but most of the released Ach is hydrolysed n the synaptic cleft to choline and acetate by the enzyme acetylcholinersterase (AchE)

Acetylcholine ——————————->choline + acetate
Acetylycholinesterase

Question 15

Neurone muscular junction process

Answer 15

Action potential in motor neurone reaches terminals
Ca?*
• Terminal depolarises
• Voltage-gated Ca?+ channels open
• Calcium influx causes vesicles of
Synaptic cleft
ACh to fuse with membrane, releasing ACh into synaptic cleft
• ACh diffuses to interact with nicotinic receptors
Na*
• ACh binding to receptors causes ion channel to open
• Cations can move through
• Nat depolarises muscle fibre;
causes action potential
Action potential
Na*
Ca?* channel
Presynaptic
terminal
ACh-
Receptor molecule
The
NMJ continued
• Following transmitter release and depolarisation of the sarcolemma, this membrane generates an action potential in the muscle fibre.
• The action potential travels along the sarcolemma, depolarising the T tubules and the sarcoplasmic reticulum where Ca++ is stored. Calcium is released into the sarcoplasm and contraction then occurs.
• Calcium is then pumped back into the SR and the muscle relaxes again.

Question 16

Modification of cholinesterase activity:

Answer 16

• if ach cannot be hydrolylsed and builds up at the junction, the receptors and the muscle are over stimulated: initially this causes uncontrolled muscle contraction, then receptor desensitisation then muscle paralysis.
  
  • some nerve gases, such as sarin, used in warfare to position and incapacitate individuals, act by inhibiting acetylcholinesterase.
    -in addition to the acetylcholinesterase at the N-M junction there is a less selective, pseudocholinesterase, widely distributed in tissues and body fluids.
    -AchE is located on and around the post-synaptic membrane, and has its active site facing into the synaptic cleft. Hydrolysis of ach takes approximately 1msec.
    -the choline produced is actively transported back into the axon terminal to be re-used to synthesis new ach: this process is called reuptake.
    -only ONE Action potential reaching the N-M junction is needed to release enough ach to stimulate the muscle
    -in some other types of cholinergic synapse multiple action potentials are required to stimulated to post-synaptic cell.

Question 17

Modifying transmission at the neuromuscular junction:

Answer 17

various substances both natural and synthetic are able to block the actions of ach or prevent its release ,or inhibit its degradation.
-agents which block the nicotinic cholinergic receptors on the motor end plate induce muscular paralysis
-neuromuscular transmission can be promoted by agents which inhibit the actions of cholinesterase at the junction. However if the dosage of cholinesterase is too great it allows the transmitter acetylcholine to accumulate in excessive quantities.
-prolonged depolarisation of the post-junctional membrane can then occur making the junction inexcitable

Question 18

Different toxins/poisons at the neuromuscular junction

Answer 18

Toxin/baceria/inhibits Ach release:

Tubocurarine- tree gum- blocks nicotinic receptors
A-bungarotoxin- snake venom- inhibits release
B-bungarotoxin- snake venom- blocks receptors
Tetrodotoxin- puffer fish- blocks na+ channels
Saxitoxin- Protozoa- blocks na+ channels
Nerve gas- sarin- inhibits AChe (ENZYME BREAKS DOWN THE ACh)
Neostigmine- bean- inhibits AChe (ENZYME BREAKS DOWN THE ACh)

Question 19

Botulinum toxin:

Answer 19

-derives from clostridium which is a anaerobe found in soil mainly, can be absorbed orally, consumption of contaminated canned or bottled foods or through skin wounds via entry of bacteria.
-inhibits acetylcholine release and affects both the autonomic system and somatic motor nerves. Thee is autonomic dysfunction,muscle weakness and eventually respiratory failure. The toxin is so potent that a single molecule can inhibit the excocyosis of acetylcholine at an axon terminal.

Question 20

Saxitoxin:

Answer 20

-is very potent toxin produced by dinoflagellates, unicellular organisms which grow fast when conditions are right, forming a ‘red tide’
-shellfish are filter feeders and take in the organisms during feeding. If people then eat these shellfish a paralytic shellfish poisoning develops.
-saxitoxin selectively blocks sodium channels leading to muscle paralysis.

Question 21

Sarin:

Answer 21

-it is a irreversible acetylcholinesterase inhibitor and is extremely toxic.
- acetylcholine accumulates at the cholinergic junction and there is a excessive stimulation of muscle, spontaneous loss of control coma and respiratory failure.

Question 22

Curare:

Answer 22

• obtained from plants (vines and trees) growing in
  Tropical forests in South Africa
  -its a mixture of alkaloids and s used locally as an arrow poison-major alkaloid responsible for its neuromuscular blocking properties is d-tubocurarine.
  -the toxin action of tubocurarine results from blockade of the nicotninc cholinoreceptors on the muscle endplate: death is due to the respiratory muscle paralysis.

Question 23

Tetrodotoxin:

Answer 23

-found in puffer fish, in japan known as fugu. Many people eat this, although said to be tasty some tissues (mainly ovary and liver), contain high concentrations of tetrodotoxi which selectively blocks sodium channels and therefore prevents the generation of action potentials in nerves.
-chefs have to be properly listened to make this.

Question 24

Organopphosphorous insecticides:

Answer 24

-angents are irreversible cholinesterase inhibitors.
-among compounds in commercial use are malathion and parathion the latter is the most common cause of serious poisonining incidents.
-cholinesterase inhibition due to phosphorylation of the enzyme results in excessive accumulation of acetylcholine at all cholinergic synapses -there is massive stimulation of the autonomic system which results in excessive bronchial and salivary secretion, diarrhoea, sweating and other symptoms
-central effects of acetylcholine excess include; confusion, agitation, coma
-at the neuromuscular junction excessive acetylcholine leads to repeated, uncontrolled contraction and then skeletal muscular weakness.
- respiratory failure due to weakness of the diaphragm and intercostal muscles can occur so patients mat need respiratory support.
-if poisoning is detected early a drug pralidoxime is used to re activate the cholinesterase enzyme so that the hydrolysis oof the excess acetylcholine then proceeds.

Question 25

Neostigmine:

Answer 25

-closely related to the anti cholinesterase physostigmune which was originally extracted from the calabar bean grown in Nigeria.
-Neostigmine is used therapeuticallly and inhibits the hydrolysis of acetylcholine at the neuromuscular function and this is a useful effect in clinical situations where cholinergic transmission is failing.

Question 26

Other toxins:

Answer 26

black widow spider venom affects the neuromuscular junction by causing a greatly increased release of acetylcholine which deselected the synaptic vesicles and the female is deadly than the male.
-the spider causes pain, cramping and rigidity of muscles but it not generally fatal in an adult

Question 27

Diseases of neuromuscular transmission :

Answer 27

Myasthenia gravis:
-produce antibodies to nicotninic receptors, antibodies bind to the nicotinic receptor to produce a complex. No of nicotinic receptors at the N-M junction decrease up to 90%
-motor neurones release normal amounts of A ch but few receptors so little contraction even when the movement is quite small eg raising the eyelids. Most common patients are 20-40 years female.

Problem first occurs in the small muscles of the
Face, starting with the eyelids which begin to drip
-after that there’s double vision
- disease progresses patients may have difficulty
In smiling, chewing and swallowing. Their speech may
Become slurred and their arms become progressively
Weaker interring with daily tasks.

Question 28

Treatment of myasthenia gravis:

Answer 28

It’s with aceytylcholinersterase inhibitors

Alternatively a proportion of the antibodies can be removed from blood by plasmapheresis. This process involves taking a blood sample which is centrifuge to remove the plasma. The plasma is discarded, and the patient’s blood cells are suspended in fresh plasma to be returned to the circulation.

Immunosuppressants drugs are sometimes given and a minority of patients, who have problems with their thymus gland, will require surgery to remove it.

Question 29

Clinical uses of drugs affecting NMJ:
Drugs that enhance transmission

Answer 29

Drugs that enhance transmission
Myasthenia gravis, Neostigmine increases activation through inhibiting AChE
Alzheimer’s disease- the most common cause of senile dementia. Patients show progressive mental deterioration associated with loss of cholinergic neurones in the CNS. One treatment which is effective for a time in mild disease is an AchEI, eg Donepezil.
War gases & insecticides (e.g. dyflos, parathion) also act this way, thus can poison person
Botulinum toxin (Botox). Used to reduce painful muscle spasms and in cosmetic surgery to reduce lines and deep wrinkles
May be used in treatment of myasthenia gravis, glaucoma, and to reverse effect of a neuro-muscular blocking drug (e.g. after surgery)

Question 30

Clinical uses of drugs affecting NMJ:
Drugs that block transmission

Answer 30

Curare (from tubocurarine), used in surgery to antagonise the nicotinic receptor on the muscle to produce complete muscle relaxation/paralysis in anaesthetised patients, particularly abdominal surgery.
Very short acting agents may also be used during intubation of patients (inserting a tracheal cannula for breathing support).

Question 31

Muscle relaxants- non-depolarising neuromuscular blockers

Answer 31

These drugs compete with acetylcholine for nicotinic receptors on the muscle end plate, so they obstruct the binding of Ach to the nicotinic receptors

Receptor activation and ion channel opening are therefore inhibited. Eg tubocurarine.
Blockade by non-depolarising agents can be reversed by allowing high concentrations of Ach to accumulate at the synaptic cleft.
This can be achieved by using acetylcholinesterase inhibitors.

Question 32

Muscle relaxants- depolarising neuromuscular blockers

Answer 32

These drugs cause a prolonged depolarisation of the end plate membrane. Eg suxamethonium.

Since the depolarisation lasts a long time, the junction does not return to its resting state after an action potential, and no further action potentials are able to stimulate the muscle.

The blockade of nerve transmission will be intensified if there is more acetylcholine at the junction, so the anticholinesterases enhance this type of neuromuscular block.

Suxamethonium chloride (also known as succinylcholine, scoline, or colloquially as sux) is a medication widely used in emergency medicine and anaesthesia to induce muscle relaxation, usually to make endotracheal intubation possible.

Trade name: Anectine, and may be referred to as “sux” for short.
Suxamethonium acts as a depolarizing neuromuscular blocker. It imitates the action of Ach at the NMJ, acting on nicotinic receptors, but it is not degraded by acetylcholinestrase but by butyrylcholinestrase, a plasma cholinesterase. This hydrolysis by butyrylcholinesterase is much slower than that of acetylcholine by acetylcholinesterase.

Prolonged depolarisation causes neuromuscular blockade

Question 33

Indications and dose of Suxamethonium chloride

Answer 33

Neuromuscular blockade (short duration) during surgery and intubation
By intravenous injection Adult
1–1.5mg/kg.
Unlicensed use