Disc 4 Quiz Flashcards
What is the primary cause of Spinal Muscular Atrophy (SMA)?
SMA is caused by mutations in the SMN1 gene, leading to deficiency of the SMN protein, which is essential for motor neuron survival.
what does spinal muscular atrophy cause? (symptoms)
muscle weakness - loss of motor neurons and muscle atrophy
which muscles type are more affected than the other by the severe form of SMA?
the proximal muscles are more affected than distal muscles
what is the amplitude of the EPC determined by? (2 things)
- number of synaptic vesicles released after nerve stimulation (quantal content)
- amplitude of the muscle response to the transmitter released from a single vesicle (quantal amplitude)
what happens to NMJ postsynaptic terminals as they mature? what does it do + how
They increase in size and sophistication - they develop multiple folds.
this is believed to amplify the action of Ach due to the high density of sodium channels in the depths of the folds
What causes SMA?
mutation of survival motor neuron + deficiency of the SMN protein
What did examining the electrophysiology reveal?
NMJ synapses remain well connected late into the disease BUT there is a reduced density and release of synaptic vesicles
purpose of ringer solution
to maintain the environment for the muscle
Which muscle groups were examined?
distal intramuscular nerves in the tibialis anterior, paraspinal, intercostal, and diaphragm muscles.
How does SMA affect motor neurons and muscles over time?
It leads to motor neuron degeneration, which in turn causes muscle atrophy and weakness, especially in proximal muscles.
What are some key pathological findings in SMA autopsy studies?
Loss of anterior horn cells (motor neurons), reduced axon diameter in ventral roots, and muscle fiber atrophy.
Why is studying NMJs in SMA mice important for understanding the disease?
NMJ dysfunction may precede motor neuron death, making it an early and potentially treatable feature of SMA.
What type of SMA mouse model was used in this study?
The hSMN2/Δ7SMN/mSmn−/− mouse model, which mimics severe SMA and dies around 2 weeks of age.
What were the main techniques used to study NMJ structure and function?
Electrophysiology, electron microscopy (EM), immunohistochemistry (IHC), and reverse transcription PCR (RT-PCR).
How was synaptic transmission measured in this study?
By recording endplate currents (EPCs) and miniature EPCs (MEPCs) using voltage-clamp techniques.
What is the significance of using electron microscopy (EM) in NMJ studies?
It allows visualization of synaptic vesicles, neurofilaments, and NMJ ultrastructure, providing insights into presynaptic defects.
What was surprising about NMJ innervation in SMA mice?
Unlike ALS, most NMJs remained innervated, even in late-stage SMA.
Which muscles showed the most denervation in SMA mice?
The intercostal (IC) and paraspinal (PS) muscles, which correlate with severe weakness in human SMA patients.
Why is the level of NMJ denervation in SMA different from diseases like ALS?
In SMA, NMJs remain connected but dysfunctional, whereas in ALS, axons degenerate early, leading to NMJ disconnection.
How were endplate currents (EPCs) affected in SMA mice?
EPC amplitudes were reduced by about 50%, meaning weaker muscle activation.
What does reduced quantal content at SMA NMJs indicate?
Fewer vesicles are released per nerve impulse, leading to weaker synaptic transmission.
How does increased synaptic facilitation suggest a lower probability of vesicle release?
Synapses with low release probability show greater facilitation during repetitive stimulation, which was observed in SMA NMJs.
What changes in synaptic vesicles were observed in SMA mice?
A 56% reduction in vesicle density and 32% fewer docked vesicles at the presynaptic membrane.
What role might neurofilament (NF) accumulation play in NMJ dysfunction?
NF buildup may interfere with vesicle trafficking and synaptic function, leading to impaired neurotransmitter release.
How does the delay in switching from fetal to adult acetylcholine receptors affect neurotransmission?
Fetal AChRs remain active longer, causing prolonged EPC decay times, which disrupts synaptic efficiency.
How does SMA affect myofiber size and composition?
SMA myofibers are smaller, and mature muscle proteins (MyHC IIb) are reduced, indicating delayed muscle development.
What changes were observed in myosin heavy chain (MyHC) expression in SMA muscle?
Increased perinatal MyHC expression and decreased adult MyHC isoforms, especially MyHC IIb.
Why are the intercostal and paraspinal muscles particularly affected in SMA?
These muscles rely heavily on continuous motor activity and are more dependent on synaptic integrity, making them more vulnerable.
What is the significance of NMJ dysfunction occurring before motor neuron degeneration in SMA?
It suggests that synaptic defects rather than neuron loss may be a primary driver of muscle weakness, offering a potential early treatment target.
How could therapies targeting NMJ function help SMA patients?
Enhancing synaptic vesicle release or stabilizing NMJs could improve muscle strength even if motor neuron loss continues.
What does this study suggest about the potential role of cytoskeletal defects in SMA?
NF accumulation and actin dysfunction might disrupt vesicle transport, contributing to NMJ failure.
How do findings in SMA mice compare to observations in other neuromuscular diseases like ALS and LEMS?
ALS: NMJs degenerate early, while SMA NMJs remain connected but functionally impaired.
LEMS: Both diseases show impaired vesicle release, but LEMS is due to autoimmune calcium channel dysfunction, whereas SMA results from SMN protein deficiency.
Summarize the key findings of this study in one sentence.
SMA causes early NMJ dysfunction due to reduced synaptic vesicle release, leading to muscle weakness before motor neuron degeneration occurs.
How do the findings in this study challenge previous assumptions about SMA progression?
It was previously thought that motor neuron death drives muscle weakness, but this study suggests that NMJ dysfunction is an earlier and primary cause.
If you were to design a treatment based on these results, what aspect of NMJ function would you target?
Enhancing synaptic vesicle release, stabilizing AChRs, or reducing neurofilament accumulation to improve neurotransmission.
