2-Synaptic & Junctional Transmission-Dec 2016_061557.pdf

This document details events at the neural muscular junction

1. SYNAPTIC AND JUNCTIONAL
TRANSMISSION
By MusengeE. M.
(13/12/2016)
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2. Outline
1.Introduction
2.Objectives
3.Synaptic transmission
4.Electrical events at the synapses
5.Neuro-muscular Transmission
6.References
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3. 1. Introduction
•Synapses are the junctions where presynaptic
cell terminates on the postsynaptic cell
•The NS uses both electrical and chemical
signals to send information from one cell to
another cell at the synapses
•There are “two” types of synapses; chemical
and electrical synapses:
i.Chemical Synapses (Majority): Asynaptic
cleft separates the terminal of the
presynaptic cell from the postsynaptic cell
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4. Introduction cont…
ii.Electrical Synapses: Membranes of the
presynaptic and postsynaptic neurons come close
together, and gap junctions form between the cells
iii.Conjoint synapses (Few): Transmission is both
electrical and chemical exist (Barrett et al., 2012)
•When postsynaptic cell is a neuron, summation of
all the excitatory and inhibitory effects determines
outcome
•Thus, synaptic transmission is a complex process
that permits the gradingand adjustmentof neural
activity necessary for normal function
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5. Electrical & Chemical synapses
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6. 13/12/2016 MME 6

7. 2. Objectives
•At the end of the lesson, students should be
able to;
I.Describe synaptic transmission
II.Explain the electrical events at synapses
III.Describe neuromuscular junction
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8. 3. Synaptic transmission
i.Types of Chemical Synapses
Axoaxonalsynapse: Presynaptic neuron end
on axons of postsynaptic neurons
Axodendrticsynapse: Presynaptic neuron end
on dendritic spines or directly on the shafts of
dendrites
Axosomaticsynapse: Presynaptic neuron end
on the soma of postsynaptic neuron
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9. Synaptic transmission cont..
ii.Structure of chemical synapse
•Anatomic structure of synapses varies considerably in
the different parts of the mammalian NS
•It has threeparts:
a.Presynaptic cell
•Presynaptic fibre ends are generally enlarged to form
synaptic knobs
•Presynaptic terminal contain many mitochondria, as well
as many membrane-enclosed vesicles, which contain
neurotransmitters (NTs)
•In cerebraland cerebellar cortex, endings are commonly
located ondendritesand frequently on dendritic spines
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10. Synaptic knob
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11. Synaptic transmission cont…
•Occasionally, on soma form basket cells of the
cerebellumand autonomic ganglia
•In other locations, they intertwinewith the
dendrites of the postsynaptic cell (climbing
fibres of the cerebellum) or end on the
dendrites directly (apical dendrites of cortical
pyramidal cells)
•On average, each neuron divides to form over
2000 synaptic endings, making communication
between neurons extremely complex
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12. Dendritic spines
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13. Synaptic transmission cont…
•Synapses are dynamic structures,
increasing and decreasing in complexity
and numberwith use and experience
•In cerebral cortex, 98% of the synapses are
on dendritesand only 2% are on soma
•In spinal cord, proportion of endings on
dendrites is less
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14. Synaptic transmission cont…
•Types of synaptic vesicles
i.Small, clear synaptic vesicles (recycle): Contain
acetylcholine (ACh), glycine, gamma-
aminobutylicacid (GABA), or glutamate
ii.Small vesicles (recycle): Have a dense core that
contain catecholamines(noradrenaline,
dopamine)
iii.Large vesicles (Soma): Have a dense core that
contain neuropeptides(enkephalins,
endorphins, substance P)
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15. Synaptic transmission cont…
•NT Classification by chemical structure
i.Acetylcholine(ACh)
ii.Biogenic amines/purines (catecholamines)
iii.Indolamines(amino acid derived amines e.g.
serotoninand histamine)
iv.Amino acids (glycine, glutamate, GABA)
v.Neuropeptides(enkephalins, endorphins,
substance P)
•NB: Red=Excitatory; Blue=Inhibitory
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16. Small synaptic vesicle cycle in
presynaptic nerve terminals
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17. Synaptic Transmission Cont…
•NTs are released by exocytosis
•Active zones (membrane thickening) contain
many proteinsand rows of Ca
2+
channels
•NT release starts within 200 s.
•Neurexinandneuroliginbind pre and post
synaptic cells
•Over 1000 different neurexins are produced
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18. Presynaptic cell: Active zone
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19. Cell adhesion molecules
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20. Main proteins that interact to produce
synaptic vesicle docking and fusion in
nerve endings
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21. Synaptic transmission cont…
b.Synaptic Cleft
•Each presynaptic terminal of a chemical
synapse is separated from the postsynaptic
structure by a synaptic cleft that is 20 to 40
nmwide (Barrett et al., 2012)
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22. Synaptic transmission cont…
c.Postsynaptic Cell
•Has many NT receptors in its membrane, and
postsynaptic density
•Postsynaptic density is an ordered complex of
specific receptors, binding proteins, and
enzymesinduced by postsynaptic effects
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23. Postsynaptic density
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Post Synaptic Density

24. Synaptic transmission cont…
•Characteristics of Synaptic Transmission
i.Synaptic delay: 0.5 msdelayis observed between the
activities of pre and postsynaptic cells
ii.One-Way Conduction: Generally permit conduction of
impulses in one direction only, from the presynapticto
the post-synaptic neurons
iii.Synaptic fatigue: Repeated stimulation of presynaptic
neuron at relatively high frequency, eventually ceases
response of postsynaptic neuron
iv.Convergence and divergence: Inputsto the cell are
multiple e.g. in spinal motor neurons; some inputs come
directly from dorsal root, some from long descending
spinal tracts, and many from interneurons
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25. Dorsal root ganglion
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26. 4. Electrical events in
postsynaptic neurons

27. i. Generation of AP in postsynaptic neuron
a.Excitatory Postsynaptic Potential (EPSP):Produced by
depolarisation of the postsynaptic cell membrane
immediately under the presynaptic ending
•Excitatory NTs opens Na
+
or Ca
2+
ion channels in the
postsynaptic membrane, producing an inward current
•EPSP due to activity in one synaptic knob is small, but
the depolarisations produced by each of the active
knobs summate
•EPSPs are produced by stimulation of some inputs,but
stimulation of other inputs produces hyperpolarising
responses, hence Inhibitory Postsynaptic Potentials
(IPSPs)
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28. EPSPs and IPSPs cont…
b.IPSP:Can be produced by a localised increase in Cl
–
transport
•When an inhibitory synaptic knob becomes active,
the released NT triggers the opening of Cl
–
channels
in the area of the postsynaptic cell membrane under
the knob, thus E
Mincreases
•Decreased excitability of the neuron during IPSP is
due to movement of theE
Maway from the firing
level, thus, more excitatory activity is necessary to
reach the firing level
•When the E
M is at E
Cl, the potential disappears
and at more negative E
M, it becomes positive
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29. EPSPs and IPSPs cont…
•E.g., they can be produced by opening of K
+
channels,with movement of K
+
out of the
postsynaptic cell, or by closure of Na
+
or Ca
2+
channels
•Slow EPSPs and IPSPshave been described in
autonomic ganglia,cardiacand smooth muscle,and
cortical neurons
•Postsynaptic potentials have a latency of 100 to 500
msand last several seconds (Barrett et al., 2012).
•Slow EPSPs are generally due to decreases in K
+
conductance,and the slow IPSPs are due to increases
in K
+
conductance
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30. ii. Types of summation
a.Temporal summation: Repeated afferent
stimuli by a single presynaptic neuron
causing new EPSPs before previous EPSPs
have decayed
b.Spatial summation: Activity is present in
more than one synaptic knob at the same
time and activity in one synaptic knob
summates with activity in another to
approach the firing level
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31. PSPs and Summation
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32. iii. Presynaptic inhibition and facilitation
•Presynaptic Inhibition in CNS: The process is mediated by
neurons whose terminals are on excitatory endings,
forming axoaxonalsynapses.
•Three mechanisms of presynaptic inhibition
a.Activation of presynaptic receptors increases Cl
–
conductance, and this has been shown to decrease the
size of the APs reaching the excitatory ending
b.Ca
2+
entry and consequently the amount of excitatory
transmitter released; voltage-gated K
+
channels are also
opened, and the resulting K
+
efflux also decreases the
Ca
2+
influx
c.Evidence for direct inhibition of transmitter release
independent of Ca
2+
influx into the excitatory ending
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33. 5. Neuromuscular transmission

34. i. Neuromuscular Junction (NMJ)
•NMJ: Specialised area where a motor neuron
terminates near midpoint of skeletal muscle fibre
•Skeletal muscle fibres are innervated by large,
myelinated nerve fibres that originate from large
motor neurons in the anterior horns of the spinal cord
•Each nerve fibre, after entering the muscle belly,
normally branches and stimulates from 3to several
100skeletal muscle fibres (Hall, 2012).
•AP initiated in muscle fibre by the nerve signal travels
in both directionstoward the muscle fibre ends
•With the exception of about 2% of the muscle fibres,
there is only one such junction per muscle fibre (Ibid)
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35. NMJ and secretion of ACh
Figure 9.7 (a-c)

36. Detailed NMJ
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37. Motor endplate (MEP)
•MEP: Nerve fibre forms a complex of branching
nerve terminals that invaginate into the surface of
the muscle fibre but lie outside themuscle fibre
plasma membrane
•MEP is coveredby one or more Schwann cells that
insulateit from thesurrounding fluids
•Synaptic cleft between the synaptic gutter and axon
terminalis 20 to 30nm wide
•Gutter bottom has subneural clefts, which greatly
increase the surface areaat which the synaptic
transmitter can act
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38. Motor Unit: Nerve-muscle functional unit
Figure 9.12 (a)

39. MEP Cont…
•Axon terminal has many mitochondriathat supply ATP
used for synthesis of ACh
•ACh in turn excites the muscle fibre membrane
•ACh is synthesised in the cytoplasmof the terminal
axon, but it is absorbed rapidly into many small
synaptic vesicles, about 300,000of which are normally
in the terminals of a single end plate
•Synaptic space contain large quantities of
acetylcholinesterase, which destroys ACh a few
millisecondsafter it has been released from the
synaptic vesicles
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40. Secretion of ACh by nerve terminals
•On reaching the NMJ, by a nerve impulse, about 125
vesicles of ACh are released from the terminals into
the synaptic space
•On the inside surface of the neural membrane are
linear dense bars
•To each side of each dense bar are voltage-gated Ca
2+
channels
•When an AP spreads over the terminal, Ca
2+
channels
open and allow Ca
2+
ions to diffuse from the synaptic
space to the interior of the nerve terminal
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41. Linear dense bars
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42. Secretion of ACh By nerve terminals
cont…
•Ca
2+
ions, in turn, are believed to exert an attractive
influence on the ACh vesicles, drawing them to the
neural membrane adjacent to the dense bars
•The vesicles then fuse with the neural membrane
and empty their ACh into the synaptic space by the
process of exocytosis
•It has been suggested that the effective stimulus for
causing ACh release from the vesicles is entry of Ca
2+
ionsand that ACh from the vesicles is then emptied
through the neural membraneadjacent to the dense
bars
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43. Effect of ACh on the postsynaptic muscle
fibre membrane to open ion channels
•Each receptor is a protein complex that has a total
molecular weight of 275,000 Da
•The complex comprises 5 subunit proteins; 2 alpha
proteins and 1 each of α, β, and γproteins
•These protein molecules penetrate all the way through
the membrane, lying side by side in a circle to form a
tubular channel
•The channel remains constricted, until 2 ACh molecules
attachrespectively to the 2 αsubunit proteins
•This causes a conformational change that opens the
channel
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44. ACh effect cont…
•The opened ACh channel has a diameter of about
0.65 nm, which is large enough to allow the
important +ve ions; Na
+
,K
+
, and Ca
++
to move easily
through the opening
•Conversely, -ve ions e.g. Cl
-
ions, do not pass through
because of strong -ve charges in the mouth of the
channel that repelthese -ve ions
•In practice, far more Na
+
ions flow through the ACh
channels than any other ions, for two reasons;
•First, there are only 2 +ve ions in large concentration:
Na
+
ions in the ECF, and K
+
ions in the ICF
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45. ACh effects cont…
•Second, the very -ve potential on the inside of the muscle
membrane, –80 to –90 mV, pulls the +vely charged Na
+
ionsto the inside of the fibre, while simultaneously
preventing efflux of the +vely charged K
+
ions when they
attempt to pass outward
•Principal effect of opening the ACh-gated channels is to
allow large #s of Na
+
ions to pour to the inside of the
fibre, carrying with them large numbers of +ve charges
•This creates a local +ve potential change inside the
muscle fibre membrane, called the end plate potential
(EPP).
•In turn, this EPP initiates an AP that spreads along the
muscle membraneand thus causes muscle contraction
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46. Destruction of released ACh by
acetlycholinestrase
•ACh, once released into the synaptic space, continues to
activate the ACh receptors as long as the ACh persists in
the space
•However, it is removed rapidly by 2 means:
i.Most of the ACh is destroyed by the enzyme
acetylcholinesterase (AChE), which is attached mainly
to the spongy layer of fine connective tissue that fills
the synaptic space between the presynaptic nerve
terminal and the postsynaptic muscle membrane
ii.A small amount of ACh diffuses out of the synaptic
space and is then no longer available to act on the
muscle fibre membrane
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47. Destruction of released Ach by
acetlycholinestrase cont…
•The short time that the ACh remains in the
synaptic space, a few milliseconds at most,
normally is sufficient to excite the muscle fibre
•Then the rapid removal of the ACh prevents
continued muscle re-excitationafter the
muscle fibre has recovered from its initial AP
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48. Safety factor for transmission at the NMJ;
Fatigue of the NMJ
•Normally, each impulse thatarrives at NMJ causes about3
times as much EPP as thatrequired to stimulate the muscle
fibre
•Thus, normal NMJ is said to have a highsafety factor
•But, stimulation of the nerve fibreat rates greater than 100
times per second for severalminutes often diminishes the
number of ACh vesicles so much that impulses fail to pass into
themuscle fibre, hence fatigue of NMJ, and it is the same
effect that causes fatigueof synapses in the CNS when the
synapses are overexcited
•Under normal functioningconditions, measurable fatigue of
the NMJ occurs rarely, and even then only at the most
exhausting levels of muscle activity (Hall, 2012)
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49. Drugs that enhance or block
transmission at the NMJ
i.Drugs that stimulate the muscle fibre by ACh-like action:
Many compounds, including methacholine, carbachol,and
nicotine, have the same effect on the muscle fibre as does
Ach
ii.Drugs that stimulate the NMJ by inactivating AChE: Three
particularly well knowndrugs,neostigmine, physostigmine,
anddiisopropylfluorophosphate, inactivate the AChEin the
synapses so that it no longerhydrolyses Ach
iii.Drugs that block transmission at the NMJ: Curariform
drugs e.g. D-tubocurarine, blocksthe action of ACh on the
muscle fibre ACh receptors, thus preventing sufficient
increase in permeability of the muscle membrane channels
to initiate an AP
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50. Diseases of the NMJ
i.Myasthenia gravis: Aserious and sometimes
fatal disease in which skeletal muscles are
weak and tire easily due to formation of
circulating antibodies to the muscle type of
NAChRs
ii.Lambert-Eaton Syndrome: Lambert-Eaton
syndrome resembles myasthenia gravisand is
a relatively rare condition
•Muscle weakness is caused by an autoimmune
attack against one of the Ca
2+
channelsin the
nerve endings at the NMJ
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51. ii. Nerve endings in smooth muscle
•Cholinergic postganglionic nerve fibres contain
clear vesicles, whereas others contain
characteristic dense-core vesicles that contain
noradrenaline
•Distinguishable end plates or other postsynaptic
specializations are absent
•Nerve fibres run along the membranes of smooth
muscle cells and sometimes groove their surfaces
•Multiple branches of the noradrenergic and,
presumably, the cholinergic neurons have
varicositiesand contain synaptic vesicles
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52. Smooth muscle synapse en passant

53. Smooth muscle synapse en passant
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54. Nerve endings in smooth muscles cont…
•In noradrenergic neurons, the varicosities are
about 5mm apart, with up to 20,000 varicosities
per neuron
•NT is apparently liberated at each varicosity, that is,
at many locations along each axon
•This arrangementpermits one neuron to innervate
many effector cells
•Synapse en passant: Type of contact in which a
neuron forms a synapse on the surface of another
neuronor a smooth muscle cell and then passes on
to make similar contacts with other cells
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55. Junctional potentials
•In smooth muscles in which noradrenergic discharge is
excitatory, stimulation of noradrenergic nerves produces
discrete partial depolarisations that look like small EPPs
and are called excitatory junction potentials (EJPs)
•EJPs summatewith repeated stimuli
•Similar EJPs are seen in tissues excited by cholinergic
discharges
•In tissues inhibited by noradrenergic stimuli,
hyperpolarisinginhibitory junction potentials (IJPs) are
produced by stimulation of the noradrenergic nerves
•Junctional potentials spread electrotonically
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56. Nerve endings in cardiac muscles
•The cholinergic and noradrenergic nerve fibres
end on the SA node, the AV node, and the bundle
of His
•Noradrenergic fibres also innervate the
ventricular muscle
•The exact nature of the endings on nodal tissue is
not known
•In the ventricle, the contacts between the
noradrenergic fibres and cardiac muscle fibres
resemble those found in smooth muscle
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57. Denervation Hypersensitivity (DH)
•DH: Motor nerve to skeletal muscle is cut and
allowed to degenerate, and the muscle gradually
becomes extremely sensitive to ACh
•DH is also seen in smooth muscle
•Smooth muscle, unlike skeletal muscle, does not
atrophy when denervated, but it becomes
hyperresponsive to the chemical mediator that
normally activates it e.g. response of denervated
iris
•Denervated exocrine glands, except for sweat
glands, also become hypersensitive
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58. 6. References
•Barrett E. Kim, Barman M. Susan, Boitano
Scott and Brooks L. Heddwen,(2012).
Ganong’s Review of Medical Physiology, 23
rd
Ed., San Francisco: McGraw-Hill Companies
Inc.
•Hall, J. E., (2012). Guyton’s Text Book of
Medical Physiology, Philadelphia: Elsevier Inc.
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