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Signal Transmission Between the Neurons

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Title: Signal Transmission Between the Neurons


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
Chemical Synapse
Electrical 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
18
(3) Storage
in vesicles
19
Terminal Button
Dendritic Spine
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.

39
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40
3 Synaptic Inhibition
  • Presynaptic inhibition
  • Amount of excitatory NT released is decreased by
    effects of second neuron, whose axon makes
    synapses with first neurons 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
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
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 active
  • B more likely to fire
  • Add a 3d neuron

48
Presynaptic Inhibition
Excitatory Synapse
  • Axon-axon synapse
  • C is inhibitory

49
Presynaptic Inhibition
Excitatory Synapse
  • 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 active
  • B more likely to fire

52
Presynaptic Facilitation
Excitatory Synapse
  • C active (excitatory)
  • more NT from A when active (MechanismAP 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
EPSP
  • Depolarization
  • more likely to fire

Vm
-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
Spatial Summation
  • Multiple synapses

vm
-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
Temporal Summation
  • Repeated stimulation
  • same synapse

Vm
-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

73
Specificity of drugs
Drug B
Drug A
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
  • directly controls channel
  • fast
  • Metabotropic channel
  • second messenger systems
  • receptor indirectly controls channel

80
(1) Ionotropic Channels
neurotransmitter
NT
81
Ionotropic Channels
82
Ionotropic Channels
NT
83
Ionotropic Channels
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
87
G protein direct control
Pore
88
(2.2) G protein Protein Phosphorylation
external signal nt
external signal NT
norepinephrine
GS
2d messenger
2d messenger
cAMP
secondary effector
secondary effector
protein kinase
89
G protein Protein Phosphorylation
PK
90
G protein Protein Phosphorylation
ATP
cAMP
PK
91
G protein Protein Phosphorylation
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 SynapticTransmission
Purves,2001
94
Basic Neurochemistry
95
3. Some Important Transmitters
96
(1) Acetylcholine (ACh) as NT
97
Acetylcholine Synthesis
choline
acetyl CoA
98
Acetylcholinesterase (AChE)
  • Enzyme that inactivates ACh.
  • Present on postsynaptic membrane or immediately
    outside the membrane.
  • Prevents continued stimulation.

99
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100
The Life Cycle of Ach
101
Ach - Distribution
  • Peripheral N.S.
  • 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
  • Muscarine
  • Nicotine
  • Indirect
  • 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
110
(2) Monoamines as NT
111
Monoamines
  • Catecholamines
  • Dopamine - DA
  • Norepinephrine - NE
  • Epinephrine - E
  • Indolamines -
  • Serotonin - 5-HT

112
Mechanism of Action (? receptor)
113
Epi
a1
G protein
PLC
IP3
Ca2
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.

115
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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
  • 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.
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