Peer Mentoring Session 6 (Exam 2)

This week you will be researching a series of disorders and determining if a treatment would work in
those disorders and why. These disorders have to do with communication at the neuromuscular
junction. Below is a normal end- plate potential (EPP). An EPP is the voltage measured in the muscle in
response to motor neuron stimulation.

The mEPPs shown at the bottom reflect spontaneous release

from the presynaptic terminal. They are known as mini EPPs. They
are all the same size because they reflect the amount of
neurotransmitter packaged in a single vesicle. The top trace
(notice the height differences) is a summary of many vesicles
being released into the neuromuscular junction. For each of the
disorders you need to draw what the EPP will look like. Also
address whether you expect to see differences in the number of
minis or size of minis.

Here are the disorders:

Eaton-Lambert syndrome

Autoimmune disorder which attacks presynaptic calcium channels, and this makes it more difficult for
them to release neurotransmitters like Acetylcholine. Acetylcholine is required for muscle contraction.
In the diagram for Eaton-Lamber syndrome I expect to see a lower overall EPP and less frequent mEPPs
because there is less acetylcholine being released.

Mysthenia Gravis
Autoimmune disorder which causes muscle weakness especially targets acetylcholine receptors at the
neuromuscular junction. Baseline EPP is reduced but still above threshold so the amplitude of the EPP
will be lower. Mini EPPs will have the less frequent. Same amount of acetylcholine in present in the
synapse but they cannot be taken up by the receptors.
The following fall under a class of disorders known as Congenital Myasthenic Syndromes, meaning they
are genetic and due to mutations in specific genes.

Pick 2 disorders and discuss what type of theoretical treatments you think would be beneficial.

The Slow-Channel Syndrome

Dominant mutations in acetylcholine gene that leads delayed closure of acetylcholine channels.

The Fast-Channel Syndrome

A recessive mutation shortens the length of time for which the acetylcholine channels on the post-
synaptic side. This results in a results in a reduced amplitude of the EPP and a narrower graph for EPP.
SNAP25B Myasthenia
SNAP25B is a component of the SNARE protein complex. The SNARE protein is implicated in the
disassembly of vesicle to release neurotransmitters into the synapse via exocytosis on the presynaptic
side. Mutant SNAP25B results in myasthenia (muscle weakness), cortical hyperexcitability. The mutation
on the SNAP25 gene affects the SNAP25B isoform thereby preventing SNARE from cracking open the
vesicle and enabling it to fuse to the plasma membrane. I expect to see a reduction in amplitude of the
EPP and a reduction in the frequency of the miniature EP potential.

A beneficial treatment could theoretically involve gene therapy. A gene that codes for the formation of a
new protein that functions similarly to SNARE could be introduced to disassemble vesicles and facilitate
exocytosis.

Endplate Acetylcholinesterase (AChE) Deficiency

Acetylcholinesterase (AChE) is an enzyme primarily found at postsynaptic neuromuscular junctions.
AChE functions to degrade acetylcholine (EACh) thus terminating neuronal transmission and signaling
between synapses so that activation of nearby receptors by ACh is reduced. When AChE is deficient, we
witness excessive signaling in the neuromuscular junction because Ach is not broken down in the
synapse and so it accumulates. We expect to see a plot with a larger amplitude for EPP because many
more miniEPPs are contributing to the overall potential. Further, due to the concentration of
acetylcholine in the synapse, we expect to see more miniEPPs as due to vast number of receptors
available to take up the aggregating neurotransmitters.