1. General Principles of the Neuron Activities
Chapter 30
General Principles of the Neuron Activities

2. Contents Neurotransmission Neurotransmitter and Receptor
Synaptic Plasticity
Properties of the Synaptic Neurotransmission

3. Part I
NEUROTRANSMISSION

4. I Synapse 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

5. 1. 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.

6. 2. Non-synaptic chemical transmission
Sympathetic Nerve
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

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

8. Innervation of Adrenal Medulla

9. 3. 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.

10. Electrical Synapses
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

11. Electrical Synapse
Chemical Synapse
Purves, 2001

12. II The Chemical Synapse and Signal Transmission

13. II The Chemical Synapse and Signal Transmission
specialized junction that transfers nerve impulse information from a pre synaptic membrane to a postsynaptic membrane using neurotransmitters and enzymes

14. Synaptic connections ~100,000,000,000 neurons in human brain
Each neuron contacts ~1000 cells
How many synapses?

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

16. Chemical Synapses
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

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

18. Postsynaptic
Membrane
Presynaptic
Axon Terminal
Terminal
Button
Dendritic
Spine

19. (1) Precursor
Transport

20. (2) Synthesis
enzymes/cofactors _ NT

21. (3) Storage
in vesicles

22. NT
Terminal
Button
Dendritic
Spine
Vesicles
Synapse

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

24. Terminal
Button
Dendritic
Spine AP
Synapse

25. Exocytosis
Ca2+

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

27. (5) Activation

28. (6) Termination

29. (6.1) Termination by...
Diffusion

30. (6.2) Termination by...
Enzymatic degradation

31. (6.3) Termination by...
Reuptake

32. (6.4) Termination by...
Autoreceptors A

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

34. Synaptic Transmission
AP travels down axon to bouton.
Voltage Gated 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 (突触蛋白）.
Synapsins aid in the fusion of synaptic vesicles.

35. 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.

36. 2 EPSP and IPSP EPSP: Excitatory postsynaptic potential
IPSP: Inhibitory postsynaptic potential

37. EPSP
An AP arriving in the presynaptic terminal cause the release of neurotransmitter
The molecules bind and activate receptor on the postsynaptic membrane

38. 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).

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

40. 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, K+ channels
CI- influx or K+ outflux produce a hyperpolarization in the postsynaptic membrane.

41. IPSPs No threshold. Hyperpolarize postsynaptic membrane.
Increase membrane potential.
Can summate.
No refractory period.

43. 3 Synaptic Inhibition Presynaptic inhibition Postsynaptic inhibition A

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

45. Reciprocal inhibition
Postsynaptic inhibition
Reciprocal inhibition

46. 2) Recurrent inhibition
Postsynaptic inhibition
2) Recurrent inhibition

47. (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) between 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.
decrease the amount of neuro- transmitter released from B (Presynaptic inhibition) B A A A B C C

48. Mechanisms Presynaptic inhibition
• Activation of the presynaptic receptors increases CI- conductance  EPSP
to decrease the size of the AP reaching the excitatory ending 
reduces Ca2+ entry and consequently the amount of excitatory transmitter decreased.

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

50. Presynaptic Inhibition
Excitatory Synapse + A B C +
Axon-axon synapse
C is excitatory ~

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

52. 4 Synaptic Facilitation: Presynaptic and Postsynaptic

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

54. 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 ~

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

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

57. 5 Synaptic Integration EPSPs can summate, producing AP.
Spatial summation
Temporal summation

58. (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.

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

60. (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.

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

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

63. +
EPSP
IPSP - +
- 70mv -

64. 6. Divergent and Convergent Synapse

65. Divergent Synapse
A junction that occurs between a presynaptic neuron and two or more postsynaptic neurons.
The stimulation of the postsynaptic neurons depends on temporal summation.

66. Convergent Synapse
A junction between two or more presynaptic neurons with a postsynaptic neuron
The stimulation of the postsynaptic neuron depends on the spatial summation.

67. Part II Neurotransmitters and receptors

68. 1. Basic Concepts Neurotransmitter
Endogenous signaling molecules that alter the behaviour of neurons or effector cells.
Neuroreceptor:
Proteins on the cell membrane or in the cytoplasm
Could bind with specific neurotransmitters
Alter the behavior of effector cells

69. 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

70. Classical Transmitters (small-molecule transmitters)
Non-classical Transmitters
Biogenic Amines (胺)
Acetylcholine
Catecholamines
Dopamine
Norepinerphrine
Epinephrine
Serotonin (5-HT)
Amino Acids
Glutamate
GABA (-amino butyric acid)
Glycine
Neuropeptides
Neurotrophins
Gaseous messengers
Nitric oxide
Carbon Monoxide
Hydrogen sulfide

71. Classes of CNS Transmitters Primary Receptor Class
Neurotransmitter
% of
Synapses
Brain
Concentration
Function
Primary Receptor Class
Monoamines
Catecholamines: DA, NE, EPI
Indoleamines: serotonin (5-HT)
2-5
nmol/mg protein
(low)
Slow change in excitability (secs)
GPCRs
Acetylcholine (ACh)
5-10
Amino acids
Inhibitory: GABA, glycine
Excitatory: Glutamate, aspartate
15-20
75-80
μmol/mg protein
(high)
Rapid inhibition (msecs)
Rapid excitation (msecs)
Ion channels

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

73. Antagonist Drugs bind to but do not activate neuroreceptors
blocking the actions of neurotransmitters or the neuroreceptor agonists.

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

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

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

77. Neurotransmitter Co-existence
Some neurons produce both a classical neurotransmitter and a polypeptide neurotransmitter.
contained in different synaptic vesicles
be distinguished using the electron microscope.
The neuron release either the classical or the polypeptide neurotransmitter under different conditions.

78. Purves, 2001

79. Examples of Co-localized Neuropeptides and Small Molecule Neurotransmitters
Site of Co-localization
NYP NE
Neurons of the locus ceruleus （蓝斑核）; sympathetic postganglionic neurons
Dynorphin（强啡肽）; substance P; enkephalin (脑啡肽）
GABA
Striatal （纹状体）GABAergic projection neurons
VIP
ACh
Parasympathetic postganglionic neurons
CGRP
Spinal motor neurons
Neurotension（神经降压素）; CCK DA
Neurons of the substantia nigra （黑质）

80. 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

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

82. (1) Ionotropic Receptor
Channel NT
neurotransmitter

83. Ionotropic Receptor NT
Pore

84. Ionotropic Receptor NT

85. Ionotropic Receptor NT

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

87. (2.1) G protein: direct control
NT is 1st messenger
G protein binds to channel
opens or closes
relatively fast ~

88. G protein: direct control
GDP

89. G protein: direct control
GTP
Pore

90. (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

91. G protein: Protein PhosphorylationC G
GDP PK

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

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

94. SOME IMPORTANT TRANSMITTERS AND THE CORRESPONDING RECEPTORS3
SOME IMPORTANT TRANSMITTERS AND THE CORRESPONDING RECEPTORS

95. Ligand-Gated Ion Channel (LG)
Major Neurotransmitter Receptors in the CNS
Neurotransmitter
Receptor Subtypes
G Protein-Coupled (G) vs.
Ligand-Gated Ion Channel (LG) DA D1 D2 D3 D4 D5 G
NE/EPI α1 α2 β1 β2 β3
5-HT
5-HT1A
5-HT1B
5-HT1D
5-HT2A
5-HT2B
5-HT2C
5-HT3
5-HT4 LG

96. Ligand-Gated Ion Channel (LG)
Major Neurotransmitter Receptors in the CNS
Neurotransmitter
Receptor Subtypes
G Protein-Coupled (G) vs.
Ligand-Gated Ion Channel (LG)
ACh
Muscarinic M1
Muscarinic M2
Muscarinic M3
Muscarinic M4
Nicotinic G LG
Glutamate
NMDA
AMPA
Kainate
Metabotropic
GABA A B

97. (1) Acetylcholine (ACh) as NT

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

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

101. The Life Cycle of Ach

102. 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 ~

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

104. 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)

105. Ligand-Operated ACh Channels
N Receptor

106. 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 (sweat glands, skeletal muscle blood vessels - dilation)

107. G Protein-Operated ACh Channel

108. 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
Blocked by Atropine, etc.

109. Cholinergic Agonists Direct Indirect Muscarine Nicotine
AChE Inhibitors ~

110. Cholinergic Antagonists
Direct
Nicotinic - Curare
Muscarinic - Atropine

111. (2) Monoamines as NT

112. Monoamines Catecholamines – Indolamines （吲哚胺）- Dopamine - DA
Norepinephrine - NE
Epinephrine - E
Indolamines （吲哚胺）-
Serotonin - 5-HT

113. 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.

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

116. Epi a1
G protein
PLC
IP3
Ca+2

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. Mechanism of Action ( receptor)

120. Adrenergic Neurotransmission
 2 receptor
stimulated by E ..
Lungs, most other sympathetic innervate 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

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

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

123. Glutamate Neurotransmitter at 75-80% of CNS synapses
Synthesized within the brain from
Glucose (via KREBS cycle/α-ketoglutarate，a-酮戊二酸)
Glutamine （谷氨酸盐） (from glial cells)
Actions terminated by uptake through excitatory amino acid transporters (EAATs) in neurons and astrocytes

125. Glutamate Receptor Subtypes

126. Ionotropic Glutamate Receptors

127. NMDA receptor as a coincidence detector : requirement for membrane depolarization
127

128. NMDA receptor uses glycine as a co-agonist
128

129. NMDA receptor channel is blocked by phencyclidine (苯环已哌啶，PCP)
129

130. Glutamate non-NMDA receptors NMDA receptors Na+ channels open
Ca2+ channels open
(Mg2+ blockade)
removes
blockade
depolarization
Ca2+ enters
when Mg2+
is removed
postsynaptic
effects
(learning)
Ca2+dependent
K+ channels
open
reinstates blockade
repolarization

131. Non-NMDA Na+ channels open, Na+ enters and depolarizes membrane
b. Mg2+ blockade of NMDA Ca2+channels removed by membrane depolarization; Ca2+enters
Ca2+ dependent K+ channels open; membrane repolarized
d. Mg2+ blockade reinstated a b c d

132. Gamma Aminobutyric acid (GABA)
inhibitory neurotransmitter of CNS and retina.
formed by decarboxylation of glutamate .
three types of GABA receptors
GABAA & B receptors are widely distributed in CNS.
GABAC are found in retina only

133. Glutamic acid decarboxylase (GAD)
GABA Synthesis
Glutamic acid decarboxylase (GAD)
COOH
NH2 – CH – CH2 – CH2 - COOH
NH2 – CH2 – CH2 – CH2 - COOH
Glutamate
GABA

135. Subunit composition of ionotropic GABAA receptors
Five subunits, each with four transmembrane domains (like nAChR)
Most have two alpha (α), two beta (β), one gamma (γ) subunit
α2 β2 γ1 is predominant in mammalian brain but there are different combinations in specific brain regions

136. Modified from nAChR, G and G 2011

138. The metabotropic GABAB receptor
GPCRs
Largely presynaptic, inhibit transmitter release
Most important role is in the spinal cord
138

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

140. (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.
Hydrogen Sulfide (H2S)

141. Part III
SYNAPTIC PLASTICITY

142. Synaptic Plasticity Concept Classification
the ability of the synapse to change in strength in response to either use or disuse of transmission over synaptic pathways
Classification
Short term Plasticity (paired-pulse facilitation, short-term potentiation, synaptic depression)
Long-term Plasticity
Long-term potentiation (LTP)
Long-term depression (LTD)

143. Presynaptic vs. Postsynaptic
I. The size of synaptic potentials can be modulated:
by regulating the amount of transmitter released at the synapse
by regulating the size of the current generated by postsynaptic receptors.
II. Short term modulation (msecs - minutes)
Mechanism: are almost always presynaptic.
Paired-pulse facilitation (~10 to 100 msecs)
Synaptic depression (50 msecs to mins)
Post-tetanic potentiation (mins)
Long-term plasticity
Mechanisms: complex and usually both pre- and postsynaptic
LTP (30 minutes to years)
LTD (30 minutes to years)

144. Facilitation and Depression

146. Facilitation of Transmitter Release
Cause: increased mean number of quanta of transmitter released by the presynaptic terminal, probably by increasing the probability of release and perhaps increasing the number of release sites.

147. Depression of Transmitter Release
caused by depletion of vesicles from the presynaptic terminal during the conditioning train, and reduced release efficacy.

155. GENERAL PRINCIPLES OF THE REFLEX (SYNAPTIC TRANSMISSION)
Part IV
GENERAL PRINCIPLES OF THE REFLEX (SYNAPTIC TRANSMISSION)

156. Special Characteristics of Synaptic Transmission
One way conduction
Delay, 0.5 ms every synapse
Summation and occlusion
Change of frequency
Afterdischarge and feedback
Localization and generalization
Fatigue
Affected by
acidosis and alkalosis
Hypoxia
Drug

157. Occlusion

158. Afterdischarge