This document provides information about Otto Loewi's famous experiment that helped identify acetylcholine as the first neurotransmitter. It discusses how Loewi discovered that stimulating the vagus nerve of one frog heart caused it to slow down, and how the liquid bathing that heart then caused a second isolated heart to also slow down, proving the involvement of a soluble chemical transmitter. It notes Loewi called the chemical "Vagusstoff" and that it was later identified as acetylcholine. The document also briefly discusses Loewi's career and his shared Nobel Prize with Henry Hallett Dale for this seminal work establishing chemical transmission in the nervous system.

1. Lecture № 4
• BelSU
Institute of Medicine
• Department Biomedical
Sciences
• Academic year 2017/18
• Spring term
• March 24, 2018
Excitation transfer between cells.
Synapses.
Распрост ранение возбуждения между
клет ками. Синапсы.

2. Guyton And Hall
Textbook Of
Medical Physiology
P. 559–569, 85-89.

3. The concepts of
"synapse", "nexus“
Question No 1.

4. • The word synapse first appeared in 1897,
in the seventh edition of Michael Foster's
Textbook of Physiology.
• Foster was assisted in writing the volume
on the nervous system by Charles
Sherrington, who can be credited with
developing and advocating the
physiological concept of a synapse.
• The word itself however, was derived by a
Cambridge classicist, Arthur Verrall.

5. Sir Michael Foster
• 1836 –1907
• An English physiologist
• One of his most famous
students at Cambridge
was Charles Scott
Sherrington who went on
to win the Nobel Prize in
1932.

6. Sir Charles Scott
Sherrington
• 1857 – 1952
• was an English
neurophysiologist
• He received the Nobel
Prize in Physiology or
Medicine with Edgar
Adrian, 1932 for their
work on the functions
of neurons..

7. The word "synapse"
• from Greek synapsis "conjunction,"
• from synaptein "to clasp,"
• from syn- "together" and haptein "to
fasten")
• Pronunciation: /’sʌɪnaps, ‘sɪn-/
• plural synapses

8. The words "synapse“,
"synapses" and "synapsis"
• Do not confuse "synapses" and
"synapsis"
• synapses pl synapse
• Synapsis (also called syndesis) is the
pairing of two homologous
chromosomes that occurs during meiosis.

9. • synapsis

10. Synapse
is a structure that permits a neuron
to pass an excitation to another cell
(neural or otherwise).

11. • Pronunciation: /’nɛksəs/
• or a gap junction
Nexus

12. Nexus
• is a specialized
intercellular connection
between a multitude of
animal cell-types
• It directly connects the
cytoplasm of two cells, which
allows
various molecules and ions to
pass freely between cells.

13. Nexus
• (in physiology) is a
specialized intercellular
connection between a
multitude of animal non-
nerve cell-types that
transmits an excitation.

14. Classification of
synapses
Question No 2.

15. Classification of synapses
Classification Criteria: The nature of
contacting cells I
• neuron  neuron
• neuron  effector cell (myocyte,
glandulocyte)
• neuron  receptor cell of secondary
receptors (efferent synapses)
• receptor cell of secondary receptors
 neuron (afferent synapses)

16. Classification of synapses
Classification Criteria: The nature of
contacting cells II
• Neuroneuronal junction (neuron 
neuron)
• Neuromuscular junction (neuron 
myocyte)
• Neurosecretory junction (neuron 
glandulocyte)
• neuron  receptor cell of secondary
receptors (efferent synapses)
• receptor cell of secondary receptors
 neuron (afferent synapses)

17. What is the difference between primary
and secondary receptors (neurology)?
• In primary receptors, the substrate that
reacts to an external influence is
embedded in the sensory neuron itself,
which is directly (primarily) excited by the
stimulus.
• In secondary receptors, additional
specialized (receptive) cells are situated
between the acting agent and the sensory
neuron. The energy of external stimuli is
transformed into impulses in these cells.

18. An effector cell may refer to:
• The muscle, gland cell capable of
responding to a stimulus at the terminal
end of an efferent neuron or motor neuron.

19. Synaptic Physiology of
Cochlear Hair Cells
• Schematic of hair
cell with afferent
and efferent
synapses and
presumptive
calcium signals in
violet color.

20. Classification of synapses
Classification Criteria: Signal
transduction mechanism
• Electrical synapses
• Chemical synapses
• Mixed Electrical–Chemical Synapses

21. Classification of synapses
• Classification Criteria: Responses of
the postsynaptic neuron
• excitatory synapses
• inhibitory synapses

22. How are excitatory synapses diffrent
from inhibitory synapses?

23. An excitatory synapse
• is a synapse in which an action potential in
the presynaptic cell increases the
probability of an action potential occurring
in the postsynaptic cell.

24. An inhibitory synapse
• is a synapse in which an action potential in
the presynaptic cell decreases the
probability of an action potential occurring
in the postsynaptic cell.

25. An inhibitory synapse
• hyperpolarizing
• depolarizing (the inhibition of the impulse
activity is similar to that during cathodic
depression)

26. The Russian physiologist B. F.
Verigo (1883, 1888),
• significantly supplemented Pflüger’s data
• found that upon prolonged exposure to a
current the initial catelectrotonic increase
in excitability gives way to “cathodic
depression,” that is, excitability decreases,
while a decrease in excitability in the
region of the anode is converted to “anodic
exaltation.”

27. Responses of the
postsynaptic neuron
• Excitatory Postsynaptic
Potentials (EPSP)
• Inhibitory Postsynaptic
Potentials (IPSP)

28. Graph displaying an EPSP, an IPSP, and the
summation of an EPSP and an IPSP. When the
two are summed together the potential is still
below the action potential threshold.

29. A model to demonstrate the effect of Excitatory
Postsynaptic Potentials (EPSP) and Inhibitory
Postsynaptic Potentials (IPSP) on a neuron.

30. Classification of synapses
Classification Criteria: Common
presynaptic arrangements

31. Types of Synapses within the
Central Nervous System

32. Synaptic Formation and
Neural Pruning

36. Common presynaptic arrangements:
1) axon terminal branches have terminal
enlargements (called boutons or bulbs)
2) axon terminal branches feature
varicosities (for synapses “in passing”)
3) neuromuscular synapse: axon branches
have terminal ramifications that form motor
end plates on skeletal muscle fibers.

37. • Varicosity
synapses

38. Classification of
neuronal synaptic types:
Most synapses connect
• axons to dendrites,
but there are also other types of connections,
including
• axon-to-cell-body,
• axon-to-axon,
• dendrite-to-dendrite.

39. Classification of
neuronal synaptic types:
• axodendritic — axon terminal branch
(presynaptic element) synapses on a dendrite;
• axosomatic — axon terminal branch synapses
on a soma (cell body);
• axoaxonic — axon terminal branch synapses on
another axon terminal branch (for presynaptic
inhibition) or beside the initial segment of an
axon;
• dendrodendritic — dendrite synapsing on
another dendrite (very localized effect).

40. Types of synaptic
connections
• AD - axodendritic
• AS - axosomatic
• AA -axoaxonic
• DD - dendrodendritic

41. Types of synaptic connections
Classification Criteria: Localization
• Central (located in the brain and spinal
cord, ie in the central nervous system)
• Peripheral (in the peripheral nervous
system).

42. Structure of a
typical chemical
synapse
Question No 3.

43. Structure of a
typical chemical synapse

44. Events of signal transmission at
a chemical synapse

45. Excitatory and inhibitory responses in
postsynaptic cells stimulated by acetylcholine

46. Variation of the structure of
synapses.

47. Electrical synapses
• - cells connect via gap junctions:
• - membranes are separated by 2 nm
• - gap junctions link the cytosol of two cells
and provide a passageway for movement
of very small molecules and ions between
the cells - this can be measured with a
fluorescent dye and using a fluorescence
microscope to observe whether they pass
into neighboring cells

50. Electron micrograph of a thin section
through a gap junction connecting two
mouse liver cells

51. Transmission of action potentials across
electric and chemical synapses

52. Release of neurotransmitters and
the recycling of synaptic vesicles

53. Neurotransmitter - goes through a
number of separate stages in its
actions
1. Synthesis
2. Packaging into vesicles

54. 1. Synthesis
- all small chemical neurotransmitters are
made in the nerve terminal
- responsible for fast synaptic signalling
- synthetic enzymes + precursors
transported into nerve terminal
- subject to feedback inhibition (from
recycled neurotransmitters)
- can be stimulated to increase activity (via
Ca+2 stimulated phosphorylation)

55. 2. Packaging into vesicles
- neurotransmitters packaged into vesicles
- packaged in small "classical" vesicles
- involves a pump powered by a pH gradient
between outside and inside of vesicle
- pump blocked by drugs and these block
neurotransmitter release

56. Chemical synapses
• pass information directionally from a
presynaptic cell to a postsynaptic cell and
are therefore asymmetric in structure and
function.

57. One-Way” Conduction at
Chemical Synapses

58. Chemical Synapse
• Presynapse and postsynapse are well
differentiated morphologically

59. Electron photomicrograph of synaptic knob (S) ending
on a dendrite (D) in the central nervous system.
• P - postsynaptic
thickening;
• M - mitochondrion.
(x56,000).

72. Amino acid sequence of enkephalin: N-Tyr-Gly-Gly-Phe-Met-C.

73. Types of Summation

74. Types of Summation
• The combination of graded potentials (EPSPs and IPSPs) in the
post-synaptic neuron is known as summation
• Cancellation occurs when excitatory and inhibitory graded potentials
cancel each other out (no threshold potential reached)
• Spatial summation occurs when EPSPs are generated from multiple
presynaptic neurons simultaneously to reach threshold
• Temporal summation occurs when multiple EPSPs are generated
from a single presynaptic neuron in quick succession
• These summative effects determine which nerve pathways are
activated and hence lead to alternate decision-making processes

75. Excitatory vs Inhibitory Synapses

76. Fast Acting versus Slow
Acting Neurotransmission

77. Long Term Potentiation

78. Mechanism of Drug Action

79. Suppression of Pain
Perception by Endorphins

80. Effect of Drug Addiction on
Dopamine Activity

81. Major Classes of
Neurotransmitter

109. Transmitter Substances.
Loewi's experiment.
Question No 4.

110. Otto Loewi
• 1873 – 1961
• Was a German born pharmacologis
whose discovery
of acetylcholine helped enhance
medical therapy.
• The discovery earned for him
the Nobel Prize in Physiology or
Medicine in 1936 which he shared
with Sir Henry Dale.
• Нобелевская премия (1936, совместно с Г.Х. Дейлом).

111. • Before Loewi's experiments, it was unclear
whether signalling across the synapse was
bioelectrical or chemical.
• Loewi's famous experiment, published in
1921, largely answered this question.
According to Loewi, the idea for his key
experiment came to him in his sleep.

112. • Loewi dissected out of frogs two beating
hearts: one with the vagus nerve which
controls heart rate attached, the other
heart on its own.

113. Loewi's experiment

114. • Both hearts were bathed in a saline
solution (i.e. Ringer's solution). By
electrically stimulating the vagus nerve,
Loewi made the first heart beat slower.
• Then, Loewi took some of the liquid
bathing the first heart and applied it to the
second heart.

115. • The application of the liquid made the
second heart also beat slower, proving
that some soluble chemical released by
the vagus nerve was controlling the heart
rate.
• He called the unknown chemical
Vagusstoff. It was later found that this
chemical corresponded to Acetylcholin.

116. • Thirteen years later, Loewi was awarded
the Nobel Prize in Physiology or Medicine,
which he shared with Sir Henry Hallett
Dale.

117. Identification of
Neurotransmitters
Question No 5.

118. There are four main criteria for
identifying neurotransmitters:
1. The chemical must be synthesized in the
neuron or otherwise be present in it.
2. When the neuron is active, the chemical must
be released and produce a response in some
target.
3. The same response must be obtained when the
chemical is experimentally placed on the target.
4. A mechanism must exist for removing the
chemical from its site of activation after its work
is done.

119. Dale's principle
Question No 6.

120. Dale, Sir Henry Hallett,
1875-1968
• The Nobel Prize in
Physiology or
Medicine 1936
Генри Дейл

121. Dale's principle
• A neuron performs the same chemical action at
all of its synaptic connections to other cells,
regardless of the identity of the target cell.

122. However, there has been disagreement
about the precise wording.
• Some modern writers have understood the
principle
• to state that neurons release one and only one
transmitter at all of their synapses.
• to mean that neurons release the same set of
transmitters at all of their synapses.

123. Neurotransmitters
Question No 7.

124. Neurotransmitters
• are endogenous chemicals that transmit
signals from a neuron to a target cell
across a synapse.

125. • There are many different ways to classify
neurotransmitters.
• Dividing them into amino acids, peptides,
and monoamines is sufficient for some
classification purposes.

126. Major neurotransmitters:
• Amino acids: glutamate, aspartate, D-
serine, γ-aminobutyric acid (GABA),
glycine
• Gasotransmitters: nitric oxide (NO),
carbon monoxide (CO), hydrogen sulfide
(H2S)
• Monoamines: dopamine (DA),
norepinephrine (noradrenaline; NE, NA),
epinephrine (adrenaline), histamine,
serotonin (SER, 5-HT)

127. Major neurotransmitters:
• Trace amines: tyramine, octopamine,
tryptamine, etc.
• Peptides: somatostatin, substance P,
cocaine and amphetamine regulated
transcript, opioid peptides
• Purines: adenosine triphosphate (ATP),
adenosine
• Others: acetylcholine (ACh),
anandamide, etc.

128. Steps of the synaptic
transmission
Question No 8.

130. Steps of the synaptic transmission
• AP on the pre-synaptic neuron
• opening of voltage-gated calcium channels
• increase in [Ca2+]
• migration and fusion of vesicles containing the
neurotransmitter
• neurotransmitter release
• diffusion of the neurotransmitter in the synaptic cleft
• binding of neurotransmitter to receptors on the post-
synaptic cell
• change in the permeability (membrane potential) of the
postsynaptic cell

131. • Mechanism by Which an Action
Potential Causes Transmitter Release
from the Presynaptic Terminals — Role
of Calcium Ions

132. Forma of release of the mediator
depending on the concentration of calcium

133. Kiss-and-run fusion
• is a type of synaptic vesicle release where
the vesicle opens and closes transiently.
• In this form of exocytosis, the vesicle
docks and transiently fuses at the
presynaptic membrane and releases its
neurotransmitters across the synapse,
after which the vesicle can then be reused.
• Kiss-and-run differs from full fusion, where
the vesicle collapses fully into the plasma

134. Vesicle fusions frozen during
transmitter release:
• fusion pores can be seen, wide-open
vesicles are rare, late events

137. Types of agonists
Question No 9.

138. An agonist
• is a chemical capable of binding to a
receptor, such as a neurotransmitter
receptor, and initiating the same reaction
typically produced by the binding of the
endogenous substance.
• of a neurotransmitter will thus initiate the
same receptor response as the
transmitter.

139. An agonist
• may activate neurotransmitter receptors
either directly or indirectly.
• Direct-binding agonists can be further
characterized as full agonists, partial
agonists, inverse agonists.

140. Direct agonists
• act similar to a neurotransmitter by binding
directly to its associated receptor site(s),
which may be located on the presynaptic
neuron or postsynaptic neuron, or both.

141. Direct agonists
• Typically, neurotransmitter receptors are
located on the postsynaptic neuron, while
neurotransmitter autoreceptors are located
on the presynaptic neuron, as is the case
for monoamine neurotransmitters;

142. Direct agonists
• in some cases, a neurotransmitter utilizes
retrograde neurotransmission, a type of
feedback signaling in neurons where the
neurotransmitter is released
postsynaptically and binds to target
receptors located on the presynaptic
neuron.

143. Indirect agonists
• increase the binding of neurotransmitters
at their target receptors by stimulating the
release or preventing the reuptake of
neurotransmitters.

144. Types of Antagonists
Question No 10.

145. An antagonist
• is a chemical that acts within the body to
reduce the physiological activity of another
chemical substance (as an opiate);
especially one that opposes the action on
the nervous system of a drug or a
substance occurring naturally in the body
by combining with and blocking its nervous
receptor.

146. Direct-acting antagonist
• takes up space present on receptors
which are otherwise taken up by
neurotransmitters themselves.
• This results in neurotransmitters being
blocked from binding to the receptors.
• The most common is called Atropine.

147. Indirect-acting antagonist
• drugs that inhibit the release/production of
neurotransmitters
• e.g., Reserpine

148. Electrical synapse
Question No 11.

149. An electrical
• synapse is a mechanical and
electrically conductive link between
two neighboring neurons that is formed
at a narrow gap between the pre- and
postsynaptic neurons known as a gap
junction.

150. Characteristics of electrical
synapses I
• electrotonic potential change
– information is transmitted in both
directions
– the potential change spreads with
“decrement”
– information is transmitted “without time
delay”
• small molecules can also cross

151. Characteristics of electrical
synapses II.
• in special cases it can “rectify”
– cations can move in one direction, while
anions in the other
– the depolarization thus spreads in a given
direction

152. Electrical synapse