Section 2:

Signal Transmission Between the

Neurons
 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
 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.
 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
 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
 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.
 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
Electrical Synapse Chemical Synapse
Purves, 2 0 0
1. The Chemical Synapse and
Signal Transmission
• 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
 Synaptic connections

• ~100,000,000,000
neurons in human
brain
• Each neuron
contacts ~1000 cells
• Forms ~10,000
connections/cell
• How many
synapses?
• Neurotransmitter-
communication via a
chemical intermediary Chemical Synapses
called a
neurotransmitter,
released from one
neuron and influences
another
• Synaptic cleft- a small
gap between the
sending (presynaptic)
and the receiving
(postsynaptic) site
•Synaptic vesicles-
small spherical or oval
organelles contain Chemical Synapses
chemical transmitter
used in transmission

• Polarization-
communication occurs
in only one direction,
from sending
presynaptic site, to
receiving postsynaptic
site
 1. Synaptic Transmission Model
• Precursor transport
• NT synthesis
• Storage
• Release
• Activation
• Termination ~diffusion, degradation,
uptake, autoreceptors
 Presynaptic Postsynaptic
Axon Terminal Membrane

Terminal
Button Dendritic
Spine
(1) Precursor
Transport
 (2)
Synthesis
enzymes/cofactors

_
_
_

NT
(3) Storage

in vesicles
 NT

Terminal
Button Dendritic
Spine

Synapse

Vesicles
(4) Release

Terminal
Button Dendritic
Spine

Synapse Receptors
 Terminal
Button Dendritic
Spine

AP Synapse
 Exocytosis

Ca2+
Each vesicle contains one quanta of neurotransmitter
(approximately 5000 molecules) – quanta
release
(5) Activation
(6) Termination
(6.1) Termination by...
Diffusion
(6.2) Termination by...
Enzymatic degradation
(6.3) Termination by...
Reuptake
(6.4) Termination by...
Autoreceptors

A
 Autoreceptors
• On presynaptic terminal
• Binds NT
same as postsynaptic receptors
different receptor subtype
• Decreases NT release & synthesis
• Metabotropic receptors
 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.
 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.
2 EPSP and IPSP
 (1)Excitatory
p os t s y na p t ic
potential ( E P S P )
• An AP arriving in the
presynaptic terminal
cause the release of
neurotransmitter;
•The molecules bind
and active receptor on
the postsynaptic
membrane;
 (1)Excitatory
p o s t s yn ap tic
potential ( E P S P )
• 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).
• No threshold. EPSP
• Decreases resting
membrane
potential.
– Closer to threshold.
• Graded in
magnitude.
• Have no refractory
period.
• Can summate.
 (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.
• (IPSPs):
–No threshold.
–Hyperpolarize
postsynaptic
membrane.
–Increase membrane
potential.
–Can summate.
–No refractory period.
 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
 (1) Postsynaptic inhibition

• Concept: effect of inhibitory synapses on

the postsynaptic membrane.
• Mechanism: IPSP, inhibitory interneuron
• Types:
Afferent collateral inhibition( reciprocal
inhibition)
Recurrent inhibition.
1) Reciprocal inhibition Postsynaptic inhibition

Activit
y in
the
affe
rent
fibe
rs
fro
m
the
mus
cle
spin
 1) Reciprocal inhibition Postsynaptic inhibition

The latter response is

mediated by branches
of the
afferent fibers that end
on
the interneurons.

The interneurons, in turn,

secrete the inhibitory

transmitter (IPSP) at synapses on the proximal

Neurons may also inhibit Postsynaptic inhibition
themselves in a negative feedback
fashion.
2) Recurrent inhibition
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.
Concept: the inhibition occurs at the
presynaptic terminals before the (2) Presynaptic
signal ever reaches the synapse. inhibition
The basic structure: an axon-axon
synapse (presynaptic synapse), A
and B. A
Neuron A has no direct effect on
neuron C, but it exert a B
Presynaptic effect on ability of B
to Influence C.
The presynatic effect May decrease C
the amount of neuro- transmitter
released from B (Presynaptic
inhibition) or increase it
(presynaptic facilitation).
 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 • Voltage-gated K+ channels

consequently the amount of are also opened, and the
excitatory transmitter resulting K+ efflux also
decreased. decreases the Ca2+ influx.
Presynaptic Inhibition
Excitatory Synapse

A + B

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

A + B
-
C

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

A + B
-
C

• C active
• less NT from A when active
• B less likely to fire ~
4 Synaptic Facilitation: Presynaptic and
Postsynaptic
 (1) Presynaptic Facilitation
Excitatory Synapse

A + B

• A active
• B more likely to fire ~
Presynaptic Facilitation
Excitatory Synapse

A + B
+
• C active (excitatory)
C
• 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 ~
(2) Postsynaptic facilitation: neuron that has
been partially depolarized is more likely to
undergo AP.
 Record here
EPSP
+
+
• Depolarization
Vm more likely to fire ~
-65mv
- 70mv AT REST

-
Time
 5 Synaptic
• EPSPs can summate,
producing AP. Integration
– Spatial summation:
• Numerous PSP
converge on a single
postsynaptic neuron
(distance).
– Temporal
summation:
• Successive waves of
neurotransmitter
release (time).
 (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.
Spatial
+
Summation +
+
• Multiple synapses
vm
-65mv
- 70mv AT REST

-
Time
 (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.
Temporal
+
Summation
+
■ Repeated stimulation
Vm ■ same synapse ~

-65mv
- 70mv AT REST

-
Time
 (3) EPSPs & IPSPs summate
• CANCEL EACH OTHER
• Net stimulation
– EPSPs + IPSPs = net effects ~
 EPSP
+
-
IPSP

+
- 70mv
-
6. Divergent and Convergent
Synapse
 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).
 Convergent Synapse
• A junction between
two or more
Presynaptic neurons
presynaptic neurons
with a postsynaptic
neuron (the ratio of
pre to post is greater
than one).
• The stimulation of
the postsynaptic
neuron depends on Postsynaptic
the Spatial neuron

Summation.
II Neurotransmitters and receptors
 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
• 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
 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
Classical Transmitters
(small-molecule Non-classical Transmitters
transmitters)
• Biogenic Amines
• Acetylcholine
• Neuropeptides
• Catecholamines
• Neurotrophins
• Dopamine
• Gaseous messengers
• Norepinerphrine
–Nitric oxide
• Epinephrine
–Carbon Monoxide
• Serotonin
• D-serine
• Amino Acids
• Glutamate
• GABA (-amino butyric acid)
• Glycine
Agonis
tA 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.
Antagoni
st
Drugs that bind to but do not activate neuroreceptors,
thereby blocking the actions of neurotransmitters or
the neuroreceptor agonists.
• Same NT can bind to different -R
• different part of NT ~

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

Receptor A Receptor B
 Five key steps in
neurotransmission
• Synthesis
• Storage
• Release
• Receptor Binding
• Inactivation

Purves, 2 0 0 1
Synaptic vesicles
• Concentrate and
protect transmitter
• Can be docked at
active zone
• Differ for classical
transmitters (small,
clear-core) vs.
neuropeptides (large,
dense-core)
 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.
Purves, 2001
 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
 2. Receptor Activation
• Ionotropic channel
– directly controls channel
– fast
• Metabotropic channel
– second messenger systems
– receptor indirectly controls channel ~
 (1) Ionotropic
Channel NT neurotransmitter
Channels
Ionotropic
Channels
NT

Pore
Ionotropic
Channels

NT
Ionotropic
Channels
 (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 ~
 (2.1) G protein: direct control
• NT is 1st messenger
• G protein binds to channel
– opens or closes
– relatively fast ~
 G protein: direct
control

R
G

GDP
 G protein: direct
control

R
G

GTP

Pore
(2.2) G protein: Protein Phosphorylation
external signal: N
nT
t norepinephrine

Receptor  adrenergic -R
trans- primary adenylyl
GS
ducer effector cyclase

2d messenger cAMP

secondary effector protein kinase

 G protein: Protein
Phosphorylation
A
C
R
G

GDP

PK
 G protein: Protein
Phosphorylation
A
C
R
G
ATP
GTP

cAMP

PK
 G protein: Protein
Phosphorylation
A
C
R
G
ATP
GTP

cAMP
PK Pore
 (3) Transmitter Inactivation

• Reuptake by presynaptic terminal

• Uptake by glial cells
• Enzymatic degradation
• Presynaptic receptor
• Diffusion
• Combination of above
Summary of
Synaptic
Transmission

Purves,2001
eurochemistr
3. Some Important Transmitters
(1) Acetylcholine (ACh)
as NT
 Acetylcholine
Synthesis
choline
acetyltransferase

choline + acetyl CoA ACh + CoA

 Acetylcholinesterase
• Enzyme that (AChE)
inactivates ACh.
– Present on
postsynaptic
membrane or
immediately outside
the membrane.
• Prevents continued
stimulation.
The Life Cycle of Ach
 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 ~
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
 Acetylcholine
• “Nicotinic” subtype Receptor:
Neurotransmission
– 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)
 Acetylcholine
• “Muscarinic” subtype Receptor: M1
Neurotransmission
– Use of signal transduction system
• Phospholipase C, IP , DAG, cytosolic Ca++
3

– 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)
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.
 Cholinergic
• Direct Agonists
– Muscarine
– Nicotine
• Indirect
– AChE Inhibitors ~
 Cholinergic
• Direct Antagonists
Nicotinic - Curare
Muscarinic - Atropine
 Ligand-Operated ACh Channels

N Receptor
M G Protein-Operated ACh
receptor
Channel
(2) Monoamines as
NT
 Monoamines
• Catecholamines – • Indolamines -
Dopamine - DA Serotonin - 5-HT
Norepinephrine - NE
Epinephrine - E
Mechanism of Action (
receptor)
Epi
1
G protein

PLC IP3

Ca+2
 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.
 Adrenergic Neurotransmission

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

•  1 receptor
– stimulated by E, ….
– Mainly heart muscle cells,
– increased heart rate and strength
 Adrenergic
•  2 receptorNeurotransmission
– 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
 Adrenergic Neurotransmission
•  3 receptor
– stimulated by E, ….
– Adipose tissue,
– stimulation of lipolysis
 (3) Amino Acids as
NT

• Glutamate acid and aspartate acid:

– Excitatory Amino Acid (EAA)
• gamma-amino-butyric acid (GABA) and
glycine:
– Inhibitory AA
 (4) Polypeptides
• CCK: as NT
– Promote satiety following meals.
• Substance P:
– Major NT in sensations of pain.
 (5) Monoxide Gas: NO
• Nitric Oxideand
(NO) CO
– 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.