1. Section 2:
Signal Transmission Between the Neurons

2. Neurotransmission 1.Chemical synapse (Classical Synapse)
Predominates in the vertebrate nervous system
2.Non-synaptic chemical transmission
3.Electrical synapse
Via specialized gap junctions
Does occur, but rare in vertebrate NS
Astrocytes can communicate via gap junctions

3. Chemical Synapse
Terminal bouton is separated from postsynaptic cell by synaptic cleft.
Vesicles fuse with axon membrane and NT released by exocytosis.
Amount of NTs released depends upon frequency of AP.

4. Non-synaptic chemical transmission
The postganglionic neurons innervate the smooth muscles.
 No recognizable endplates or other postsynaptic specializations;
 The multiple branches are beaded with enlargements (varicosities) that are not covered by Schwann cells and contain synaptic vesicles;
Fig. : Ending of postganglionic autonomic neurons on smooth muscle

5. Non-synaptic chemical transmission continued
 In noradrenergic neurons, the varicosities are about 5m, with up to 20,000 varicosities per neuron;
 Transmitter is apparently released at each varicosity, at many locations along each axon;
 One neuron innervate many effector cells.
Fig. : Ending of postganglionic autonomic neurons on smooth muscle

6. Electrical Synapse
Impulses can be regenerated without interruption in adjacent cells.
Gap junctions:
Adjacent cells electrically coupled through a channel.
Each gap junction is composed of 12 connexin proteins.
Examples:
Smooth and cardiac muscles, brain, and glial cells.

7. Electrical Synapses
Electric current flow- communication takes place by flow of electric current directly from one neuron to the other
No synaptic cleft or vesicles cell membranes in direct contact
Communication not polarized- electric current can flow between cells in either direction

8. Electrical Synapse
Chemical Synapse
Purves, 2001

9. I The Chemical Synapse and Signal Transmission

10. The chemical synapse is a specialized junction that transfers nerve impulse information from a pre synaptic membrane to a postsynaptic membrane using neurotransmitters and enzymes

11. Synaptic connections ~100,000,000,000 neurons in human brain
Each neuron contacts ~1000 cells
Forms ~10,000 connections/cell
How many synapses?

12. Neurotransmitter- communication via a chemical intermediary called a neurotransmitter, released from one neuron and influences another
Synaptic cleft- a small gap between the sending (presynaptic) and the receiving (postsynaptic) site
Chemical Synapses

13. Synaptic vesicles- small spherical or oval organelles contain chemical transmitter used in transmission
Polarization- communication occurs in only one direction, from sending presynaptic site, to receiving postsynaptic site
Chemical Synapses

14. 1. Synaptic Transmission Model
Precursor transport
NT synthesis
Storage
Release
Activation
Termination ~diffusion, degradation, uptake, autoreceptors

15. Postsynaptic
Membrane
Presynaptic
Axon Terminal
Terminal
Button
Dendritic
Spine

16. (1) Precursor
Transport

17. (2) Synthesis
enzymes/cofactors _ NT

18. (3) Storage
in vesicles

19. NT
Terminal
Button
Dendritic
Spine
Vesicles
Synapse

20. (4) Release
Terminal
Button
Dendritic
Spine
Synapse
Receptors

21. Terminal
Button
Dendritic
Spine AP
Synapse

22. Exocytosis
Ca2+

23. Each vesicle contains one quanta of neurotransmitter (approximately 5000 molecules) – quanta release

24. (5) Activation

25. (6) Termination

26. (6.1) Termination by...
Diffusion

27. (6.2) Termination by...
Enzymatic degradation

28. (6.3) Termination by...
Reuptake

29. (6.4) Termination by...
Autoreceptors A

30. Autoreceptors On presynaptic terminal Binds NT
same as postsynaptic receptors
different receptor subtype
Decreases NT release & synthesis
Metabotropic receptors

31. Synaptic Transmission
AP travels down axon to bouton.
VG Ca2+ channels open.
Ca2+ enters bouton down concentration gradient.
Inward diffusion triggers rapid fusion of synaptic vesicles and release of NTs.
Ca2+ activates calmodulin, which activates protein kinase.
Protein kinase phosphorylates synapsins.
Synapsins aid in the fusion of synaptic vesicles.

32. Synaptic Transmission (continued)
NTs are released and diffuse across synaptic cleft.
NT (ligand) binds to specific receptor proteins in postsynaptic cell membrane.
Chemically-regulated gated ion channels open.
EPSP: depolarization.
IPSP: hyperpolarization.
Neurotransmitter inactivated to end transmission.

33. 2 EPSP and IPSP

34. (1)Excitatory postsynaptic potential (EPSP)
An AP arriving in the presynaptic terminal cause the release of neurotransmitter;
The molecules bind and active receptor on the postsynaptic membrane;

35. (1)Excitatory postsynaptic potential (EPSP)
Opening transmitter-gated ions channels ( Na+) in postsynaptic- membrane;
Both an electrical and a concentration gradient driving Na+ into the cell;
The postsynaptic membrane will become depolarized(EPSP).

36. EPSP No threshold. Decreases resting membrane potential.
Closer to threshold.
Graded in magnitude.
Have no refractory period.
Can summate.

37. (2) Inhibitory postsynaptic potential (IPSP)
• A impulse arriving in the presynaptic terminal causes the release of neurotransmitter;
•The molecular bind and active receptors on the postsynaptic membrane open CI- or, sometimes K+ channels;
• More CI- enters, K+ outer the cell, producing a hyperpolarization in the postsynaptic membrane.

38. (IPSPs): No threshold. Hyperpolarize postsynaptic membrane.
Increase membrane potential.
Can summate.
No refractory period.

40. 3 Synaptic Inhibition Presynaptic inhibition:
Amount of excitatory NT released is decreased by effects of second neuron, whose axon makes synapses with first neuron’s axon.
Postsynaptic inhibition

41. (1) Postsynaptic inhibition
Concept: effect of inhibitory synapses on the postsynaptic membrane.
Mechanism: IPSP, inhibitory interneuron
Types:
Afferent collateral inhibition( reciprocal inhibition)
Recurrent inhibition.

42. 1) Reciprocal inhibition
Activity in the afferent fibers from the muscle spindles (stretch receptors) excites (EPSPs) directly the motor neurons supplying the muscle from which the impulses come.
Postsynaptic inhibition
At the same time, inhibits (ISPSs) those motor neurons supplying its antagonistic muscles.

43. 1) Reciprocal inhibition
The latter response is mediated by branches of the afferent fibers that end on the interneurons.
Postsynaptic inhibition
The interneurons, in turn, secrete the inhibitory transmitter (IPSP) at synapses on the proximal dendrites or cell bodies of the motor neurons that supply the antagonist.

44. Postsynaptic inhibition
Neurons may also inhibit themselves in a negative feedback fashion.
Each spinal motor neuron regularly gives off a recurrent collateral that synapses with an inhibitory interneuron which terminates on the cell body of the spinal neuron and other spinal motor neurons.
The inhibitory interneuron to secrete inhibitory mediator, slows and stops the discharge of the motor neuron.
Postsynaptic inhibition
2) Recurrent inhibition

45. (2) Presynaptic inhibition
Concept: the inhibition occurs at the presynaptic terminals before the signal ever reaches the synapse.
The basic structure: an axon-axon synapse (presynaptic synapse), A and B.
Neuron A has no direct effect on neuron C, but it exert a Presynaptic effect on ability of B to Influence C.
The presynatic effect May decrease the amount of neuro- transmitter released from B (Presynaptic inhibition) or increase it (presynaptic facilitation).
(2) Presynaptic
inhibition B A A A B C C

46. Presynaptic inhibition
The mechanisms:
• Activation of the presynaptic receptors increases CI- conductance, 
to decrease the size of the AP reaching the excitatory ending, 
reduces Ca2+ entry and consequently the amount of excitatory transmitter decreased.
• Voltage-gated K+ channels are also opened, and the resulting K+ efflux also decreases the Ca2+ influx.

47. Presynaptic Inhibition
Excitatory Synapse + A B
A active
B more likely to fire
Add a 3d neuron ~

48. Presynaptic Inhibition
Excitatory Synapse + A B C -
Axon-axon synapse
C is inhibitory ~

49. Presynaptic Inhibition
Excitatory Synapse + A B C -
C active
less NT from A when active
B less likely to fire ~

50. 4 Synaptic Facilitation: Presynaptic and Postsynaptic

51. (1) Presynaptic Facilitation
Excitatory Synapse + A B
A active
B more likely to fire ~

52. Presynaptic Facilitation
Excitatory Synapse + A B C +
C active (excitatory)
more NT from A when active (Mechanism:AP of A is prolonged and Ca 2+ channels are open for a longer period.)
B more likely to fire ~

53. (2) Postsynaptic facilitation: neuron that has been partially depolarized is more likely to undergo AP.

54. Vm EPSP + + - Record here Depolarization more likely to fire ~ Time
-65mv
- 70mv
AT REST -
Time

55. 5 Synaptic Integration EPSPs can summate, producing AP.
Spatial summation:
Numerous PSP converge on a single postsynaptic neuron (distance).
Temporal summation:
Successive waves of neurotransmitter release (time).

56. (1) Spatial Summation
The accumulation of neurotransmitter in the synapse due the combined activity of several presynaptic neurons entering the Area (Space) of a Convergent Synapse.
A space (spatial) dependent process.

57. vm Spatial + Summation + + - Multiple synapses Time -65mv - 70mv
AT REST -
Time

58. (2) Temporal Summation
The accumulation of neurotransmitters in a synapse due to the rapid activity of a presynaptic neuron over a given Time period.
Occurs in a Divergent Synapse. (explain later)
Is a Time (Temporal) dependent process.

59. Vm Temporal + Summation + - Repeated stimulation same synapse ~ Time
-65mv
- 70mv
AT REST -
Time

60. (3) EPSPs & IPSPs summate
CANCEL EACH OTHER
Net stimulation
EPSPs + IPSPs = net effects ~

61. +
EPSP
IPSP - +
- 70mv -

62. 6. Divergent and Convergent Synapse

63. Divergent Synapse
A junction that occurs between a presynaptic neuron and two or more postsynaptic neurons (ratio of pre to post is less than one).
The stimulation of the postsynaptic neurons depends on temporal summation).

64. Convergent Synapse
A junction between two or more presynaptic neurons with a postsynaptic neuron (the ratio of pre to post is greater than one).
The stimulation of the postsynaptic neuron depends on the Spatial Summation.
Presynaptic neurons
Postsynaptic neuron

65. II Neurotransmitters and receptors

66. 1. Basic Concepts of NT and receptor
Neurotransmitter: Endogenous signaling molecules that alter the behaviour of neurons or effector cells.
Neuroreceptor: Proteins on the cell membrane or in the cytoplasm that could bind with specific neurotransmitters and alter the behavior of neurons of effector cells

67. Vast array of molecules serve as neurotransmitters
The properties of the transmitter do not determine its effects on the postsynaptic cells
The properties of the receptor determine whether a transmitter is excitatory or inhibitory

68. A neurotransmitter must (classical definition)
Be synthesized and released from neurons
Be found at the presynaptic terminal
Have same effect on target cell when applied externally
Be blocked by same drugs that block synaptic transmission
Be removed in a specific way
Purves, 2001

69. Classical Transmitters (small-molecule transmitters)
Non-classical Transmitters
Biogenic Amines
Acetylcholine
Catecholamines
Dopamine
Norepinerphrine
Epinephrine
Serotonin
Amino Acids
Glutamate
GABA (-amino butyric acid)
Glycine
Neuropeptides
Neurotrophins
Gaseous messengers
Nitric oxide
Carbon Monoxide
D-serine

70. Agonist A substance that mimics a specific neurotransmitter,
is able to attach to that neurotransmitter's receptor
and thereby produces the same action that the neurotransmitter usually produces.
Drugs are often designed as receptor agonists to treat a variety of diseases and disorders when the original chemical substance is missing or depleted.

71. Antagonist Drugs that bind to but do not activate neuroreceptors,
thereby blocking the actions of neurotransmitters or the neuroreceptor agonists.

72. Same NT can bind to different -R different part of NT ~
Receptor A
Receptor B

73. Specificity of drugs
Drug B
Drug A NT
Receptor A
Receptor B

74. Five key steps in neurotransmission
Synthesis
Storage
Release
Receptor Binding
Inactivation
Purves, 2001

75. Synaptic vesicles Concentrate and protect transmitter
Can be docked at active zone
Differ for classical transmitters (small, clear-core) vs. neuropeptides (large, dense-core)

76. Neurotransmitter Co-existence (Dale principle)
Some neurons in both the PNS and CNS produce both a classical neurotransmitter (ACh or a catecholamine) and a polypeptide neurotransmitter.
They are contained in different synaptic vesicles that can be distinguished using the electron microscope.
The neuron can thus release either the classical neurotransmitter or the polypeptide neurotransmitter under different conditions.

77. Purves, 2001

78. Receptors determine whether:
Synapse is excitatory or inhibitory
NE is excitatory at some synapses, inhibitory at others
Transmitter binding activates ion channel directly or indirectly.
Directly
ionotropic receptors
fast
Indirectly
metabotropic receptors
G-protein coupled
slow

79. 2. Receptor Activation Ionotropic channel Metabotropic channel
directly controls channel
fast
Metabotropic channel
second messenger systems
receptor indirectly controls channel ~

80. (1) Ionotropic ChannelsNT
neurotransmitter

81. Ionotropic Channels NT
Pore

82. Ionotropic Channels NT

83. Ionotropic Channels NT

84. (2) Metabotropic Channels
Receptor separate from channel
G proteins
2d messenger system
cAMP
other types
Effects
Control channel
Alter properties of receptors
regulation of gene expression ~

85. (2.1) G protein: direct control
NT is 1st messenger
G protein binds to channel
opens or closes
relatively fast ~

86. G protein: direct control
GDP

87. G protein: direct control
GTP
Pore

88. (2.2) G protein: Protein Phosphorylation
external signal: nt
external signal: NT
norepinephrine
b adrenergic -R
Receptor
trans-
ducer
primary
effector
Receptor
trans-
ducer
primary
effector GS
adenylyl
cyclase
2d messenger
2d messenger
cAMP
secondary effector
secondary effector
protein kinase

89. G protein: Protein PhosphorylationC G
GDP PK

90. G protein: Protein PhosphorylationC G
GTP
ATP
cAMP PK

91. G protein: Protein PhosphorylationC G
GTP
Pore
ATP P
cAMP PK

92. (3) Transmitter Inactivation
Reuptake by presynaptic terminal
Uptake by glial cells
Enzymatic degradation
Presynaptic receptor
Diffusion
Combination of above

93. Summary of Synaptic Transmission
Purves,2001

94. Basic Neurochemistry

95. 3. Some Important Transmitters

96. (1) Acetylcholine (ACh) as NT

97. Acetylcholine Synthesis
acetyltransferase
choline
+ acetyl CoA
ACh + CoA

98. Acetylcholinesterase (AChE)
Enzyme that inactivates ACh.
Present on postsynaptic membrane or immediately outside the membrane.
Prevents continued stimulation.

100. The Life Cycle of Ach

101. Ach - Distribution Peripheral N.S. Central N.S. - widespread
Excites somatic skeletal muscle (neuro-muscular junction)
Autonomic NS
Ganglia
Parasympathetic NS--- Neuroeffector junction
Few sympathetic NS – Neuroeffector junction
Central N.S. - widespread
Hippocampus
Hypothalamus ~

102. Ach Receptors
ACh is both an excitatory and inhibitory NT, depending on organ involved.
Causes the opening of chemical gated ion channels.
Nicotinic ACh receptors:
Found in autonomic ganglia (N1) and skeletal muscle fibers (N2).
Muscarinic ACh receptors:
Found in the plasma membrane of smooth and cardiac muscle cells, and in cells of particular glands .

103. Acetylcholine Neurotransmission
“Nicotinic” subtype Receptor:
Membrane Channel for Na+ and K+
Opens on ligand binding
Depolarization of target (neuron, muscle)
Stimulated by Nicotine, etc.
Blocked by Curare, etc.
Motor endplate (somatic) (N2),
all autonomic ganglia, hormone producing cells of adrenal medulla (N1)

104. Acetylcholine Neurotransmission
“Muscarinic” subtype Receptor: M1
Use of signal transduction system
Phospholipase C, IP3, DAG, cytosolic Ca++
Effect on target: cell specific (heart , smooth muscle intestine )
Blocked by Atropine, etc.
All parasympathetic target organs
Some sympathetic targets (endocrine sweat glands, skeletal muscle blood vessels - dilation)

105. Acetylcholine Neurotransmission
“Muscarinic” subtype: M2
Use of signal transduction system
via G-proteins, opens K+ channels, decrease in cAMP levels
Effect on target: cell specific
CNS
Stimulated by ?
Blocked by Atropine, etc.

106. Cholinergic Agonists Direct Indirect Muscarine Nicotine
AChE Inhibitors ~

107. Cholinergic Antagonists
Direct
Nicotinic - Curare
Muscarinic - Atropine

108. Ligand-Operated ACh Channels
N Receptor

109. G Protein-Operated ACh Channel
M receptor
G Protein-Operated ACh Channel

110. (2) Monoamines as NT

111. Monoamines Catecholamines – Indolamines - Dopamine - DA
Norepinephrine - NE
Epinephrine - E
Indolamines -
Serotonin - 5-HT

112. Mechanism of Action ( receptor)

113. Epi a1
G protein
PLC
IP3
Ca+2

114. Norepinephrine (NE) as NT
NT in both PNS and CNS.
PNS:
Smooth muscles, cardiac muscle and glands.
Increase in blood pressure, constriction of arteries.
CNS:
General behavior.

116. Adrenergic Neurotransmission
1 Receptor
Stimulated by NE, E,
blood vessels of skin, mucosa, abdominal viscera, kidneys, salivary glands
vasoconstriction, sphincter constriction, pupil dilation

117. Adrenergic Neurotransmission
2 Receptor
stimulated by, NE, E, …..
Membrane of adrenergic axon terminals (pre-synaptic receptors), platelets
inhibition of NE release (autoreceptor),
promotes blood clotting, pancreas decreased insulin secretion

118. Adrenergic Neurotransmission
1 receptor
stimulated by E, ….
Mainly heart muscle cells,
increased heart rate and strength

119. Adrenergic Neurotransmission
 2 receptor
stimulated by E ..
Lungs, most other sympathetic organs, blood vessels serving the heart (coronary vessels),
dilation of bronchioles & blood vessels (coronary vessels), relaxation of smooth muscle in GI tract and pregnant uterus

120. Adrenergic Neurotransmission
 3 receptor
stimulated by E, ….
Adipose tissue,
stimulation of lipolysis

121. (3) Amino Acids as NT Glutamate acid and aspartate acid:
Excitatory Amino Acid (EAA)
gamma-amino-butyric acid (GABA) and glycine:
Inhibitory AA

122. (4) Polypeptides as NT CCK: Substance P:
Promote satiety following meals.
Substance P:
Major NT in sensations of pain.

123. (5) Monoxide Gas: NO and CO
Nitric Oxide (NO)
Exerts its effects by stimulation of cGMP.
Involved in memory and learning.
Smooth muscle relaxation.
Carbon monoxide (CO):
Stimulate production of cGMP within neurons.
Promotes odor adaptation in olfactory neurons.
May be involved in neuroendocrine regulation in hypothalamus.