A breif overview of Anatomy of neuromuscular junction to understand the disese related to pre-post syneptic disorders.

1. Anatomy of
neuromuscular junction
Shehzad Hussain
31/10/2017

2. Index:
1. Introduction
2. Introduction as RNS
3. NMJ physiology
4. Number of quanta

3. Introduction:
• The use of repetitive nerve stimulation (RNS) dates
back to the late 1800s, when Jolly made visual
observations of muscle movement that occurred after
nerve stimulation. Although his initial studies were
done with submaximal stimuli and mechanical rather
than electrical measurements were made, Jolly noted
a decrementing response following RNS in patients
with myasthenia gravis and correctly concluded that
the disorder was peripheral.

4. INTRODUCTION TO RNS
Subsequently, RNS has been refined and validated as
one of the most useful electrodiagnostic (EDX) tests in
the evaluation of patients with suspected
neuromuscular junction (NMJ) disorders. RNS should
be performed whenever there is a possible diagnosis of
myasthenia gravis, Lambert-Eaton myasthenic
syndrome, or botulism.

5. Cont...
CLINICAL PRESENTATION:
•It also should be considered in any patient who
presents with fatigability, proximal weakness,
dysphagia, dysarthria, or ocular abnormalities,
which are clinical symptoms and signs
suggestive of a possible NMJ disorder

6. NORMAL NEUROMUSCULAR JUNCTION
PHYSIOLOGY
• The NMJ essentially forms an electrical-chemical-
electrical link between nerve and muscle (Figure).
The chemical neurotransmitter at the NMJ is
acetylcholine (ACH). ACH molecules are packaged
as vesicles in the presynaptic terminal in discrete
units known as quanta; each quantum contains
approximately 10,000 molecules of ACH. The
quanta are located in three separate stores.
The primary, or immediately available, store consists
of approximately 1,000 quanta located just beneath
the presynaptic nerve terminal membrane.

7. Cont…
This store is immediately available for release.
The secondary, or mobilization, store consists
of approximately 10,000 quanta that can
resupply the primary store after a few seconds.
Finally, a tertiary, or reserve, store of more than
100,000 quanta exists far from the NMJ in the
axon and cell body.

8. Cont…
• When a nerve action potential invades and depolarizes
the presynaptic junction, voltage-gated calcium channels
are activated, allowing an influx of calcium. The infusion
of calcium starts a complicated interaction of many
proteins that ends in the release of ACH from the
presynaptic terminal. The greater the calcium
concentration inside the presynaptic terminal, the more
quanta are released. ACH then diffuses across the
synaptic cleft and binds to ACH receptors (ACHRs) on the
postsynaptic muscle membrane. The postsynaptic
membrane is composed of numerous junctional folds,
effectively increasing the surface area of the membrane,
with ACHRs clustered on the crests of the folds.

12. Cont…
The binding of ACH to ACHRs opens sodium channels,
resulting in a local depolarization, the endplate potential
(EPP). The size of the EPP is proportional to the amount
of ACH that binds to the ACHRs.
In a process similar to the generation of a nerve action
potential, if the EPP depolarizes the muscle membrane
above threshold, an all-or-none muscle fiber action
potential is generated and propagated through the
muscle fiber. Under normal circumstances, the EPP
always rises above threshold, resulting in a muscle fiber
action potential.

13. How an action potential is generated?
NMJ.WMV

14. • The amplitude of the EPP above the threshold
value needed to generate a muscle fiber action
potential is called the safety factor. In the
synaptic cleft, ACH is broken down by the
enzyme acetylcholinesterase, and the choline
subsequently is taken up into the presynaptic
terminal to be repackaged into ACH. During slow
RNS (2-3 Hz) in normal subjects, ACH quanta are
progressively depleted from the primary store,
and fewer quanta are released with each
successive stimulation.

15. Cont…
The corresponding EPP falls in amplitude, but because of
the normal safety factor, it remains above threshold to
ensure generation of a muscle fiber action potential
with each stimulation. After the first few seconds, the
secondary (mobilization) store begins to replace the
depleted quanta with a subsequent rise in the EPP. The
physiology of rapid RNS (10-50 Hz) in normal subjects is
more complex. Depletion of quanta from the
presynaptic terminal is counterbalanced not only by the
mobilization of quanta from the secondary store but
also by the accumulation of calcium.

16. Cont..
Normally, it takes about 100 ms for calcium to be actively
pumped out of the presynaptic terminal. If RNS is rapid
enough so that new calcium influx occurs before the
previously infused calcium has been fully pumped out,
calcium accumulates in the presynaptic terminal, causing
an increased release of quanta. Normally, this
accumulation of calcium predominates over depletion,
leading to an increased number of quanta being released
and a correspondingly higher EPP. However, the result is
the same as with any other EPP above threshold: an all-
or-none muscle fiber action potential is generated.

17. Cont…
• Thus, the effects of slow and rapid RNS are very
different at the molecular level, yet in normal
subjects the result is the same: the consistent
generation of a muscle fiber action potential. In
pathologic conditions where the safety factor is
reduced (i.e., baseline EPP is reduced but still above
threshold), slow RNS will cause depletion of quanta
and may drop the EPP below threshold, resulting in
the absence of a muscle fiber action potential.

18. Cont…
In pathologic conditions where baseline EPP is below
threshold and a muscle fiber action potential is not
generated, rapid RNS may increase the number of
quanta released, resulting in a larger EPP, so that
threshold is reached. A muscle fiber action potential
then is generated where one had not been present
previously. These concepts form the basis of the
decrements with slow RNS and increments with rapid
RNS that are seen in NMJ disorders.

19. The end