3.4 Somatic motor system and the NMJ

Question 1

Structure of a chemical synapse

CNS synapses often occur between neurons
In chemical synapses, neurotransmitters from synaptic vesicles are released from presynaptic terminal onto the post-synaptic compartment.
- In CNS, the postsynaptic compartment is frequently another neuron and these synapses serve as cell-cell junctions for communication.
- Axons from one neurons which sends information will form a synapse with the receiving neuron, also called a postsynaptic cell.
- When a sending neuron depolarizes and fires an action potential, neurotransmitters released from presynaptic terminal will bind to receptors in the postsynaptic membrane
- The postsynaptic membrane contains neurotransmitter receptors that triggers a signaling cascade in the postsynaptic neuron when neurotransmitters are released
- There are different types of neurotransmitters and each have their own unique receptors as well as their downstream signaling pathways.
- For example in the CNS, glutamate and GABA are neurotransmitters that binds to glutamatergic and GABAergic receptors respectively.
- The synapse is now thought more as a tripartite structure with ________________ These glia contribution toward synapse function and also stability.

Answer 1

pre-synaptic and post-synaptic compartments as well as glial protrusions (astrocytes) that wrap around the synapse.

Question 2

Structure of the neuromuscular junction
How does a neuromuscular junction compare to a CNS synapse
- First, a neuromuscular junction is also considered a ______________ synapse in that there is neurotransmitter is released into the synaptic cleft which then binds to the appropriate receptors in the postsynaptic membrane. Unlike a CNS synapse between two neurons, the NMJ post-synaptic membrane is a _________________
- Action potentials from axons that form a contact with the muscle cell trigger the release of acetylcholine at the NMJ leading to muscle contraction.
- Schwann cells myelinate axons of motor neurons and also form a protective sheath around the boutons.
The target muscle cells consist of connective tissue called a __________ which usually has many invaginations and fold to increase the total surface area of the postsynaptic membrane. In that way, neurotransmitter secretion will bind to more receptors that line the invaginations.

Answer 2

chemical;

different cell type, most commonly a muscle cell;

basal lamina

Question 3

Cholinergic Synapse

Cholinergic synapses release acetylcholine. The NMJ is a type of cholinergic synapse where the post-synaptic cell is a muscle cell.

• Cholinergic synapses can also be found in the CNS and destruction of cholinergic synapses is thought to be responsible for many neurodegenerative diseases
• Acetylcholine is synthesized from choline and acetyl-CoA . In cholinergic synapses, ________________ is required to make ACh. CAT is heavily concentrated at the synapse and converts choline, which is transported from outside the cell into the synapse and Acetyl-CoA into ACh.
• Once produced, ACh is immediately transported into vesicles via the _______________
• _____________ triggers the docking of the synaptic vesicle and release of ACh. Once ACh is release, it is metabolized by _______________ in the cleft and the choline is recycled to the presynaptic terminal.
• Acetylcholine is released from synaptic vesicles and binds to acetylcholine receptors (AChR) that are either nicotinic or muscarinic.

Answer 3

acetylcholine transferase (CAT);

vesicular transporter (VaChT).;

Calcium influx;

acetylcholinesterase

Question 4

Nicotinic acetylcholine receptor (nAChR)
- Ionotropic
- Binds to _____________ etc.
- ____________ ion channel (Na+, K+ and Ca2+)
- Fast transmission.
- Pre-post ganglionic synapse in ANS
It is called nicotinic because nicotine preferentially bind to the receptor. Many of the pre-postganglionic synapses in the ANS have nicotinic receptors.

Answer 4

nicotine, carbachol;

Ligand-gated;

Question 5

Muscarinic acetylcholine receptor (mAChR)

• Metabotropic
• Binds to _______________ etc.
• G-protein coupled receptors because the G-proteins act as secondary messengers to initiate a signaling cascade leading to upregulation of ___________
• Slower transmission.
• Parasympathetic division (muscle, heart glands): The parasympathetic postganglionic neurons that innervate the target organs often have this particular signaling pathway.

Answer 5

muscarine, atropine, pilocarpine;

cGMP

Question 6

what is curare (d-tubocurarine)

Answer 6

Plant toxin that is a competitive inhibitor of nicotinic ACh receptors.

Question 7

what is α-bungarotoxin

Answer 7

Snake toxin that is competitive and highly irreversible inhibitor of nicotinic ACh receptors.

Question 8

Activation of the neuromuscular junction

1. First, an action potential propagated along the axon arrives at the presynaptic terminal
2. The depolarization of the membrane triggers activation of voltage-gated calcium channels which then triggers the influx of calcium from the extracellular environment.
3. Calcium triggers signaling cascade which leads to the fusion of synaptic vesicles at the active zone,
4. ACh is released into the synaptic cleft.
5. ACh is rapidly bound to the AChR and in this case, the nicotinic AChR ion channel allows ________________________- to flow inward to the motor end plate
6. This ion influx triggers further activation of ______________ and propagation of action potentials along muscle fiber for contraction.
7. The acetylcholine in the cleft is rapidly degraded or hydrolyzed by acetylcholinesterase.

Early experiments noted that at resting state, there is a low probability of synaptic vesicle release of ACh at the NMJ.

• This was done by recording the membrane potentials of the NMJ at resting states.
• The researchers noted these small changes in the membrane potentials which correlated with a quantal release of ACh-loaded synaptic vesicles.
• These spontaneous release of ACh and the recordings are known as ___________________

Answer 8

sodium and potassium ions;

sodium channel;

miniature end-plate potentials.

Question 9

Formation and maturation of NMJ occur in distinctive steps

1. The first stage is the approach of an _____________ from a motor neuron approaches the _____________ is it innervating. This occurs during early stages of growth and development of an organism.
2. Once growth cone reaches the myotube it forms an unspecialized but functional contact.
3. Recruitment of proteins from both presynaptic and postsynaptic terminal occurs. The nerve terminal accumulates synaptic vesicles and the __________ starts to form in the synaptic cleft.
4. As the muscle matures, multiple axons will converge at the site.
5. Eventually, all but one axon is eliminated and the NMJ matures.

_______________ during development is one of the key features of NMJ development. In early stages of development of ganglion cells and muscle, multiple axons will innervate each site. However, as animal matures, synapse elimination occur and all but one axon terminal survives. The remain synapse becomes stable and becomes more elaborate and also more complex.

Answer 9

axon growth cone; myotube;

basal lamina;

Synapse elimination

Question 10

Acetylcholine receptor (AChR) clustering is critical for NMJ assembly and function

• One of the key feature of the NMJ development is receptor clustering.
• The AChR clustering during synaptogenesis is critical for NMJ function.
• The presynaptic terminal in the NMJ secrete Agrin, a large ____________ that binds to the a component receptor ______________ which resides at the post synaptic muscle cell.
• This binding of Agrin then initiates signaling cascade to activate _____which then anchors the ACh to the cytoskeleton and also helps to cluster the AChR.
• Not surprisingly, mutations in any of these component proteins, MuSK, Rapsyn, Agrin or Lrp4 are all found in human patients and have resulted in developmental defects in skeletal or muscle development or impaired locomotion.

In one invitro experiment using cultured muscle cells, addition of agrin to a growing muscle cell induces formation of AChR cluters. The experiment shows that _____________________

Answer 10

proteoglycan;

Lrp4/MuSK;

rapsyn;

soluble agrin in the absence of presynaptic innervation is sufficient to trigger receptor clustering.

Question 11

Mysthenia Gravis: Autoantibodies target the __________________ resulting in receptor blockade, down regulation, and complement mediated destruction, thus reducing the number of receptors available to interact with the ACh

Answer 11

acetylcholine (ACh) receptor (AChR)

Question 12

Lambert-Eaton Mysthenic Syndrome
In LEMS the autoantibody target is the ____________________. Loss of this ion channel leads to a reduction in calcium entry into the nerve terminal and insufficient release of ACh

Answer 12

P/Q type voltage gated calcium channel expressed on the presynaptic nerve terminals

Question 13

In acquired neuromyotonia, autoantibodies cause down regulation of _______________on the peripheral nerve terminal. This reduction in VGKCs prolongs depolarisation of the nerve terminal, increasing the amount of ACh released from the nerve terminal and resulting in _________________.

Answer 13

voltage gated potassium channels (VGKCs) expressed ;

nerve hyperexcitability

Question 14

How does the motor cortex control movements?

Answer 14

planning, initiating and directing voluntary movements

Question 15

how does the basal ganglia control movements?

Answer 15

Initiation of intended movement and suppression of unwanted movement

Question 16

how does the cerebellum control movements?

Answer 16

coordination of ongoing movements

Question 17

how does the brainstem control movements?

Answer 17

rhythymic, stereotyped movements and postural control

Question 18

Upper motor neurons

• Upper motor neurons whose soma lies in the motor cortex sends information both to the________________ and to a lesser extent, the motor neuron pool which contains the lower motor neurons that regulate skeletal muscle contraction. These upper motor neurons are important for initiating voluntary movements and complex spatiotemporal sequences in skilled movements.
• Upper motor neurons originating in the brainstem are responsible for _________________. Their contributions also are critical for basic navigational movements and for the control of posture.

Answer 18

local circuit neurons in the spinal cord;

regulating muscle tone and for orienting the eyes, head, and body with respect to vestibular, somatic, auditory, and visual sensory information

Question 19

Somatotopic organization of lower motor neurons

Lower motor neurons are organized somatotopically: neurons innervating ___________are located from medial to lateral ventral horn of the spinal cord. For example, lower motor neurons that innervate the proximal muscles of the arm are the next most lateral, while those that innervate the distal parts of the extremities, including the hands and fingers, lie farthest from the midline.

Injection of retrograde tracers into gastrocnemius and soleus muscles in cat identified a population of lower motor neurons in the _______________ of the spinal cord that innervates these leg muscles.

A transverse section through the lumbar level of the spinal cord shows lower motor neurons forming distinct, rod-shaped clusters (motor neuron pools) in the ipsilateral ventral horn. Spinal cord cross sections and a reconstruction seen from the dorsal surface illustrate the distribution of motor neurons innervating individual skeletal muscles in both axes of the cord

There are two types of lower motor neurons found in the motor neuron pools of the ventral horn. Large motor neurons are called ________________; they innervate the striated muscle fibers that actually generate the forces needed for posture and movement.

Answer 19

proximal to distal muscles ;

lumbar/sacral region;

α motor neurons

Question 20

The alpha motor neurons

• These are the lower motor neurons of the brainstem and the spinal cord.
• Axons in the a motor neurons innervate _________________.
• Activation of a motor neurons causes muscle contraction.
• A single muscle can receive innervations from multiple 𝜶 motor neurons.

Interspersed among the α-𝜶motor neurons are smaller γ motor neurons, which innervate __________. The function of the γ motor neurons is to regulate sensory input to the spinal cord and brain stem regarding the __________________.

Answer 20

multiple fibres of the skeletal muscles;

specialized muscle fibers called muscle spindles;

length and state of the muscle

Question 21

The Motor Unit and Motor Pool

• A motor unit is a ___________________
• In the diagram, you can see two different motor units, 1 and 2. These motor units comprise of one single axon forming multiple synaptic contacts with various muscle fibers. On the right is an image of the muscle fibers and the clusters of NMJ that form from each muscle strand.
• Collectively, all the motor units that innervate a single muscle are called the _________________.

Answer 21

single motor neuron sending out projections from the spinal cord and innervating different muscle fiber strands;

motor neuron pool

Question 22

Properties of a motor unit

• It is the smallest functional unit with which to produce force.
• Humans have approximately 420,000 motor neurons and 250 million skeletal muscle fibers.
• On average each motor neuron supplies about600 muscle fibers.
• Stimulation of one motor unit causes __________________
• Different motor units coordinate for muscle contraction.

Both motor units and the α motor neurons can vary in size. Small α motor neurons innervate relatively few muscle fibers to form motor units that generate small forces, whereas large motor neurons innervate larger, more powerful motor units.

Answer 22

contraction of all the muscle fibers in that unit

Question 23

Motor units also differ in the types of muscle fibers they innervate. In most skeletal muscles, the smaller motor units comprise small “red” muscle fibers that contract slowly and generate relatively small forces; but because of their rich ________________, these small red fibers are resistant to fatigue. Small motor units innervate fewer fibers while larger units innervates more fibers to generate a much larger force during contraction

Type I: Slow (S)

• Smallest motor unit (smallest a motor neuron cell body): have the smallest diameter cell bodies, small dendritic trees, thinnest axons and also slowest conduction velocity
• Generates a smaller force for ___________________ contraction: These neurons generate a small but consistent force important for activities that require sustained muscular contraction, such as maintaining an upright posture
• Fatigued-resistant: enriched in mitochondria with abundant capillaries which is why they are resistant to fatigue because they have ample resources to generate energy

Type IIA: Fast, Fatigued-resistant (FR)

• Intermediate in size: intermediate diameter cell bodies with large dendritic trees thick axons
• Generates twice the force of Type I motor unit: have fast conduction velocity but not quite as fast as the Type IIB neurons
• Fatigue-resistant

Type IIB: Fast, Fatigable (FF)

• Large motor unit (Largest a motor neuron cell body): larger diameter cell bodies, dendritic trees, thicker axons and faster conduction velocity
• Generates a large force for brief exertions: These units are called __________________ and are especially important for brief exertions that require large forces, such as running or jumping.
• Easily fatigued: These larger α motor neurons innervate larger, pale muscle fibers that generate more force; however, they have fewer _____________ and so easily fatigued

Answer 23

myoglobin content, plentiful mitochondria, and rich capillary beds;

slower but sustained;

fast fatigable (FF) motor units;

mitochondria

Question 24

Functional properties of the motor units
The different properties of the motor units explain how the nervous system produces movements
- In most muscles, small, slow motor units have ___________ thresholds for activation than do the larger units and are ___________ active during motor acts that require sustained effort (standing, for instance). The thresholds for the large, fast motor units are reached only during rapid movements requiring great force, such as jumping.
- The functional distinctions between the various classes of motor units also explain some structural differences among muscles. For example, a motor unit in the ___________ (a muscle important for posture that comprises mostly small motor units) has an average innervation ratio of 180 muscle fibers for each motor neuron.
- Innervations also depend on how strong a force is required. For example in gastrocnemius leg muscles, a strong force is required for movement. So, each motor neuron innervates many muscle fibres. Up to 1000-2000 muscle fibers per neuron.
- ______________ has 3 muscle innervations per neuron. Force requirement extremely low but the movement is very precise, constant but does not require large amount of force.

Answer 24

lower;

tonically;

soleus;

Eye movement

Question 25

Recruitment

• Motor units are not randomly recruited.
• As input is increase, gradual tension is enhanced and recruitment occurs in fixed order by size of motor neurons.
• Size Principle: ______________
• As tension increases, larger units are recruited as more force is required.

Answer 25

Smallest units are recruited first, followed by intermediate and large.

Question 26

Rate coding

• Motor units fire at different range of frequencies.
• As firing rate increase, the force generated by the units increase.
• Single twitches at low frequencies undergo _______________ to generate a much higher force.
• At the highest firing rates, the individual muscle units are firing simultaneously to produce a _________________: there is no relaxation period between firing of action potentials.

(A) At low frequencies of stimulation (red arrows), each action potential in the motor neuron results in a single twitch of the related muscle fibers. Single muscle twitches occur around 5Hz.
(B) At higher frequencies, the twitches sum to produce a force greater than that produced by single twitches. These temporal summations occur at firing frequencies of 20Hz.
(C) At a still higher frequency of stimulation, the force produced is greater, but individual twitches are still apparent. This response is referred to as _______________ which is when neurons fire at 80 Hz.
(D) At the highest rates of motor neuron activation at 100 Hz, individual twitches are no longer apparent—a condition called fused tetanus-v that is, the tension produced in individual motor units no longer has peaks and troughs that correspond to the individual twitches evoked by the motor neuron’s action potentials.

Answer 26

temporal summation;

fused tetanus;

unfused tetanus