Week 4 Flashcards
What does a motor unit comprise of
A a-motoneuron
All extrafusal skeletal muscle fibres it supplies
What is the a-motoneurone
A specific subset of neurones of the nervous system through which all commands from the brain are relayed to skeletal muscles
What is a neuromuscular junction
The site of communication between the motoneurone and muscle
Theres 2 variants to the classification of motoneurone
Upper and lower motoneurones
Arranged strictly in series, damage to either of these leads to motoneurone signs
Where are upper motoneurones found
Reside in the brain in the cerebral cortex and travel down to the brain stem or spinal cord
Where are lower motoneurons’ cell bodies found
In the ventral horn of spinal cord grey matter or cranial nerve motor nuclei in the brain stem
What is meant by innervation
The term used to describe the normal state of nerve supply to a muscle of other target
Act of stimulating
Denervation
Depriving muscle of its nerve supply
Re-innervation
Re-growth of the nerve to re-supply the muscle
Re-innervation of the original effector organ is not always successful, most nerves reinnervate an effector organ that is different from its original target
This leads to emergence of all sorts of unexpected results
What leads to death of motoneurones
Loss or damage to the motoneurones cell body
Theres a class of diseases that target cell bodies of motoneurones
This would result in the denervation of muscles
What is poliomyelitis
Communicable infection that targets cell bodies of lower motoneurones of body
Also known as infantile paralysis
Caused by infection by polio virus
Leads to toxic infection of cell bodies of neurones of ventral horn
Any motoneurones of spinal cord are susceptible to virus
What does death of motoneurones lead to
Denervation hence paralysis of muscles they supply
Toxic infection of cell bodies of neurones of ventral horn can lead to death of dorsal horn too
What is motoneuron disease
Rare condition affecting brain and nerves
2 variants
Disease simultaneously kills both lower and upper motoneurones. Known as progressive supranuclear palsy
The disease targets only lower motoneurone
What is programmed cell death known as
Apoptosis
Which motoneurones dont undergo apoptosis under MD
Motoneurones supplying extraocular muscles
Motoneurones supplying anal sphincter
Implications of disorders of motoneurones axon and LMN signs
Loss or damage to motoneurones axon doesn’t necessarily lead to death of motoneurone
However it leads to the removal innervation to muscle- known as denervation
Complete transaction of axons of motor nerve
Exemplified by crushing injuries to limbs, stabbing injuries
Usually accidental
Often inevitable involvement of nerves supplying affected part of body
Results in denervation of muscles involved
What is Guillain-Barré syndrome
G-B syndrome is acquired as a complication following a viral infection such as common cold
Rare and serious condition mainly affects feet, hands, limbs causing numbness, weakness and pain
Demyelination of axons of motoneurones
Diabetic neuropathy leads to demyelination of axons of both sensory and motor axons
Clinical signs reverse when condition is cured or goes into remission
Clinical motor signs can return with relapse
Vision loss, muscle weakness, muscle stiffness and spasms, loss of coordination, changes in bladder and bowel function, walking problems
What is peripheral neuropathy
Type of nerve damage that can cause pain, weakness, numbness
Nerves located outside Brian and spinal cord
Implications of disorders of neuromuscular junction and LMN signs
Neuromuscular junction is necessary element to integrity of motor unit
Theres a class of diseases that target NMJ in its own right
LMN damage include weakness, muscle atrophy (wasting), and fasciculations (muscle twitching), decreased reflexes
What is the NMJ
It’s the tissue interface between motoneurone and muscle
It’s synaptic interface
Special synapse
Also called end plate
How does NMJ work
Motoneuron forms presynaptic membrane, releases acetylcholine as neurotransmitter
The muscle forms post synaptic membrane, expresses Nicotinic receptors that convert chemical messages carried by Ach
The synaptic cleft expresses enzyme acetylcholine esterase that destroys any Ach that isn’t bound to postsynaptic membrane
What does botulinum toxin do
Acts to deplete the presynaptic terminal of NMJ of its neurotransmitter
Effect of botulinum toxin is dry mouth and difficulty swallowing
What is myasthenia gravis
Rare genetic disease of neuromuscular junction
Nicotinic receptors of postsynaptic membrane of NMJ are selectively destroyed by persons immune system, blocked by antibodies. Reduced transmission of ACh, symptoms worsen then get better when rest
It affects any neuromuscular junction of body in affected individuals. Not localised
Droopy eyelids, Ptosis
Ophthalmoplegia- weakness or paralysis of eye muscles
Brings about flaccid weakness of affected muscles. Fatigability, proximal weakness
Can cause respiratory failure if muscle of respiration affected
Duchenne muscular dystrophy- genetic disorder
Genetic
Progressive muscle weakness
Defects in muscle proteins
Death of muscle tissue
Eventual death of affected individual
Lower motoneuron signs
Lesions of lower mn lead to characteristic impairments of movements
Theres a series of emergent clinical presenting signs known as LMN signs
LMN signs are very different from upn signs
Why are NMJ specialised for rapid transmission
Lots of places where the neurotransmitter is released
Lots of active zones where vesicles release contents
More than other synapses in CNS
Contain junctional folds which contain postsynaptic densities
Role of Ca2+ in excitation-contraction coupling
Calcium conc greater outside- concentration gradient
Action potential in post synaptic terminal
Depolarisation opens voltage gated calcium channels, Ca enters presynaptic terminal
So intracellular conc increases
Fusion of vesicles with presynaptic membrane, neurotransmitter (ACh) released
Ca2+ induced vesicle fusion
Calcium entry into presynaptic terminal triggers vesicle fusion
Calcium sensor is synaptotagmin (calcium binds to this and it changes shape)
Change in conformation on ca binding triggers vesicle fusion
Exocytosis of neurotransmitter
Exact mechanism is unclear
ACh transmitter end plate
ACh binds to Nicotinic ACh receptors on postsynaptic end plate membrane
2 molecules of ACh needed to bind
Ionotropic receptor/ ligand gated ion channel
NMJ- specialised synapse
Presynaptic- multiple quanta release- many vesicles releasing contents in CNS single vesicle only
Postsynaptic- junctional folds, high density of nACh receptors ( allow sodium in end plate potential), high density of voltage gated Na+ channels- action potential, end plate potential
Why is End plate potential so high
So many receptors activated by so much neurotransmitter
Large depolarisation
ACh transmitter at end plate
ACh binds to nACh receptors
Channel opens-permeable to Na+ and K+
Em muscle cell= -90mV
Na+ influx»> K+ efflux because Em«Ena whereas Em~Ek
Large driving force for sodium
EPP= -20Mv
How does the end plate potential work
EPP initiates an AP in muscle, not action potential itself
EPP decays as it moves away from end plate- Nicotinic receptors not expressed anywhere else other than end plate
AP then travels through muscle cell
Properties of EPP
Timing presynaptic AP to EPP ~1msec
EPP generated by ligand gated channels
Very large in comparison to most synaptic potentials- ,many ACh vesicles, high density of nAChRs
Threshold for AP generation easily passed- high density Na+ voltage gated channels at end plate
The postsynaptic action potential
AP invades T tubules system
Allows transmission of AP deep into muscle fibre to separate myofibrils
Propagate along muscle fibre
Where is calcium ions released from
Sarcoplasmic reticulum
Fate of ACh
ACh binds to nAChR for ~ 1ms
Released into synaptic cleft- hydrolysed by acetylcholinesterase AChE
Concentration ACh decreased rapidly
Choline taken back up to make new ACh
Choline acetyl transferase catalyses synthesis ACh in cholinergic neurones
Myesthenia gravis
Autoimmune disease which affects expression of receptors so synapse fails. Not enough nAChRs postsynaptically to get reliable transmission at this synapse which should never fail
Caused by failure of NMJ
Do not get large enough EPP to generate AP
Muscle weakness during sustained activity
What muscles first affected in myesthenia gravis
Skeletal muscle of the eye fatigue most quickly so symptoms seen here first
Eyes most active muscles in body
Treatment of myesthenia gravis
AChE inhibitors
-prolongs signal
-neostigmine-acetylcholinesterase inhibitor
Allows ACh to last longer so receptors can get enough ACh to stimulate them
Disorders of the motor unit
Death or dysfunction of the muscle gives symptoms similar to lower motoneuron signs
-characteristic impairments of movement
-flaccid muscle weakness
-hypotonia (low level of muscle tone) or atonia (lack of muscle tone)
-hyporeflexia (skeletal muscles have a decreased or absent reflex response) or areflexia (absence of deep tendon reflexes)
-denervation of muscle atrophy
-fasciculations (acute phase)
-muscle wasting
Duchenne muscular dystrophy
A genetic progressive muscle weakness. Defects in muscle protein dystrophin causes death of muscle tissue
UPN signs
Weakness
Spasticity- a condition in which there is an abnormal increase in muscle tone or stiffness of muscle, which might interfere with movement speech or be associated with discomfort or pain
Clonus
Hyperflexia
Clinical sign that would be seen in acute phase of LMN lesion before muscle atrophy
Fasciculations- caused by increased receptor concentration on muscles to compensate for lack of innervation
Consequence of denervating a skeletal muscle fibre
If a muscle cell is not reinnervated it may ultimately die
