Synapses
Of
C.n.s
By
Dr. Khaled Ibrahim
SYNAPSES
 Definition: It is the Communication (area of contact) between 2 neurons
in the central nervous system.
Types of
synapses
ELECTRICAL
SYNAPSES
CHEMICAL
SYNAPSES
1- ELECTRICAL SYNAPSES :
 Extremely rare.
 Structure:
- The
membranes
of
the
two
neurons come close together and are
held together by connecting protein
channels called “connexons”, which
contain pores that permit the passage
of ions between cells easily.
- This
allows
rapid
direct
conduction of electrical potentials
from one neuron to the next.
2- CHEMICAL SYNAPSES:
 Much more common (almost all synapses in CNS).
Presynaptic
neuron
Postsynaptic
neuron
 Presynaptic neuron: is the neuron which conduct the impulse
toward the synapse & release the chemical transmitter.
 Postsynaptic neuron: is the neuron which conduct impulse away
from the synapse.
 Physiological Anatomy: Formed of:
1) a presynaptic terminal.
2) postsynaptic membrane.
3) a synaptic cleft.
a) Presynaptic Terminal:
- It is a terminal branch of the axon of the presynaptic neuron.
- This terminal can make contact with any part of the postsynaptic neuron.
So, chemical synapses can be classified into:
Axodendritic ----> junction < > the terminal & postsynaptic dendrites.
Axosomatic -----> junction < > the terminal & postsynaptic soma.
Axoaxonic -----> junction < > the terminal & postsynaptic axon.
According to predominance: Axodendritic > Axosomatic > Axoaxonic.
But according to excitability: Axoaxonic > Axosomatic > Axodendritic.
Structure:
* Most of the terminals resemble small round or oval knobs. So, they are
called terminal buttons or synaptic knobs.
* Synaptic knob contains:
- large number of vesicles which contain the chemical transmitter
released in the synaptic cleft.
- large number of mitochondria which supply
synthesis of the transmitter substance either
energy (ATP) for
in the
endoplasmic
reticulum or the cytoplasm of the synaptic knob.
- Then the transmitter is transported into the vesicles by specific
transporters in the vesicle membrane
b) Synaptic Cleft:
- It is the narrow space separating the membrane of the synaptic knob
from the postsynaptic membrane.
- 20 to 30 nm in width.
- It is filled with thin filaments that help to bind the pre-and postsynaptic
membranes together.
c) Postsynaptic Membrane:
- It shows thickening directly opposite the synaptic knob called "active
zone".
- This active zone is the site of receptors which can bind chemical
transmitters released from the synaptic knob.
Mechanism of Synaptic Transmission
transmitter
into
the
1
• Release of the
synaptic cleft.
on
the
2
• Action of the transmitter
postsynaptic membrane.
3
• Termination of synaptic transmission.
1) Release of the transmitter into the synaptic cleft: (Role of Ca2+ ions)
 The membrane of synaptic knob contains voltage-activated Ca2+
channels near the release sites of the presynaptic membrane.
Mechanism:
 Arrival of action potential to the synaptic knob -----> depolarization of
the membrane -----> transient opening of Ca2+ channels ------> Ca2+ influx
near the release sites ------> fusion of the vesicles with the knob membrane
------> rupture to release its chemical transmitter content by "exocytosis".
 Then vesicle membrane separates from the knob membrane ----->
mobilized back to fuse with a cistern of the smooth endoplasmic reticulum
(where the chemical transmitter is synthesized) ------> inserted into packets
in the cistern membrane ------> pinched off forming new synaptic vesicles.
 The number of vesicles ruptured (& so the amount of the transmitter
released) is proportional to the intracellular Ca2+ concentration in the
synaptic knob.
i.e., ↑ intracellular Ca2+ concentration -----> ↑released transmitter & vice
versa.
 Intracellular Ca2+ concentration is increased by:
a) ↑frequency of impulses reaching the presynaptic terminal. So,
successive action potential will produce a greater response which is called
"post-tetanic potentiation".
b) ↓rate of removal of Ca2+ from the synaptic knob.
2) Action of the transmitter on the postsynaptic membrane:
The released chemical transmitter binds a SPECIFIC RECEPTOR on
the postsynaptic neuron producing a change in the postsynaptic
membrane potential known as POSTSYNAPTIC POTENTIALS
which will be SUMMATED to generate an ACTION POTENTIAL
propagated along the postsynaptic neuron.
Postsynaptic
Receptors
Ligand Gated Ionic
Channels.
G-Protein
Coupled
Receptors.
I) Ligand - Gated Ionic Channels:
I) Ligand - Gated Ionic Channels:
1) Cation Channels
2) Anion Channels
- lined by –ve charges which repel - narrow channels & don't allow the
Cl- and other anions and prevent passage of Na+, K+ and Ca+2 as their
their passage.
size is larger than the channel.
When opened, allow the passage - When opened, allow passage of
of Na+, K+ and Ca+2.
anions mainly Cl-.
-
- Allows Na+ influx > K+ efflux (7.5 - Cl- influx -----> hyperpolarization of
times) -----> depolarization of the the membrane ----> inhibition.
postsynaptic membrane --------->
stimulation.
- So, these are excitatory synapses & - So, these are inhibitory synapses &
the chemical transmitter released is the chemical transmitter released is
excitatory transmitter.
inhibitory transmitter.
Example: Acetylcholine
nicotinic receptors.
on
its Example: Glycine on its receptor.
II) G-Protein Coupled Receptors:
Chemical transmitter
GDP
Inactive adenyl
cyclase
The Transmitter binds the receptor
II) G-Protein Coupled Receptors:
1
2
3
II) G-Protein Coupled Receptors:
 These receptors are provided by specific membrane proteins which are
not ionic channels.
 These receptors use a group of proteins known as “G-proteins” which
are bound to the receptor proteins. G- proteins are the key molecule of the
system.
 G-protein molecule consists of three components; alpha(), beta (),
and gamma () components.
 They are called G-proteins as they are bound to GTP in their active form
& to GDP in their inactive form.
- Mechanism:
 A neurotransmitter binds to its specific membrane receptor -----> altered
receptor binds G-proteins ------> replacement of GDP bound to them by
GTP ( the G- protein is activated) -------> Separation of the “ component”
from the remainder of the G-protein molecule & becomes free to move
within the postsynaptic cell.
The separated active “ component” may:
1) Open specific second - messenger gated ion channels in the post synaptic
membrane: e.g. K+ channels which when opened ------> ↑ K+ efflux ----->
hyperpolarization of the postsynaptic membrane .
2) Activate particular enzyme systems ------> formation of the second
messengers, such as : c AMP, c GMP, inositol - 3 - phosphate (IP3) ,
diacylglycerol (DAG), and arachidonic acid. These systems control
many highly specific metabolic pathways in the neuron.
3) Regulate gene transcription by controlling the binding of RNA
polymerase to the gene ------> control of synthesis and production of
certain proteins within the neuron, including enzymes, receptor
molecules, and cellular structural proteins.
Postsynaptic Potentials:
 They are changes of the potential of the postsynaptic membrane as a
result of binding of a neurotransmitter to its specific receptor.
 The “postsynaptic potentials” are of two types:
(i) Excitatory postsynaptic potentials (EPSPs).
(ii) Inhibitory postsynaptic potentials (IPSPs).
(i) Excitatory postsynaptic potentials (EPSPs):
 Definition: A state of partial depolarization of the postsynaptic
membrane as a result of binding of an excitatory transmitter to its specific
receptor.
 During depolarization, membrane potential became closer to the
threshold ------> ↑ excitability of the neuron. So, this change is called
“excitatory postsynaptic potential”: (EPSP) .
 Mechanism:
1) opening of ligand-gated cation channels -----> more Na+ influx than
K+ efflux -----> depolarization.
2) Closure of K+ channels -----> ↓K+ efflux -----> depolarization.
 Characters:
1- Short duration (15 m.s.) then rapidly declines as +ve charges diffuse
out of the postsynaptic membrane to restore normal resting membrane
potential.
2- Can be summated:
- EPSP produced by a single discharge from one synaptic knob is quite
small, and produces a depolarization of about 0.5 mV.
- A depolarization of at least 10 to 20 mV is required to reach the usual
threshold for excitation of the postsynaptic neuron.
- So, EPSPs should summate to ↑the amplitude of depolarization & reach
the threshold.
- There are two types of summation: spatial summation & temporal
summation.
a) Spatial summation:
Summation of several EPSPs produced at the same time (when
more than one presynaptic is active at the same time).
b) Temporal Summation:
Summation of rapid successive EPSPs at the same site with time
interval less than 15 ms. (when one presynaptic terminal is stimulated
rapidly & repeatedly)
- In both types of summation, if the summated EPSPs reach the threshold,
an action potential is produced.
(ii) Inhibitory postsynaptic potentials (IPSPs).
 Definition: A state of hyperpolarization caused by binding of inhibitory
neurotransmitter to its specific receptor.
 During hyperpolarization, membrane potential became away from the
threshold --->
↓ excitability of the neuron. So, this change is called
“inhibitory postsynaptic potential”: (IPSP) .
 Mechanism:
1) opening of ligand - gated anion channels (Cl- channels) -----> Cl- influx ----> hyperpolarization.
2) Opening of specific K+ channels -----> ↑ K+ efflux ------>
hyperpolarization.
 Characters:
1- Short duration (15 m.s.).
2- Can be summated:
Both by spatial & temporal summation (see before)
Postsynaptic inhibition
----
Presynaptic inhibition
+++
----
Types of inhibition:
1- Postsynaptic inhibition:
- It is a type of inhibition in which the inhibitory knob of a
presynapic neuron is applied directly to a postsynaptic membrane.
- The inhibitory presynaptic terminal may be applied to any part of
the postsynaptic neuron: Axodendritic, Axosomatic, Axoaxonic
junctions.
Mechanism: see before.
Extent: affect the entire postsynaptic neuron.
2- Presynaptic Inhibition:
- It is a type of inhibition in which the inhibitory knobs of an
interneuron is applied to an excitatory presynaptic terminal.
- The inhibitory interneuron forms an axo-axonic synapse with the
presynaptic neuron.
- The inhibitory interneuron acts to modify the rate of release of the
neurotransmitter from the presynaptic neuron.
- Extent: It affects only a localized area on the postsynaptic neuron.
Mechanism:
* Most
of the inhibitory interneurons which inhibit the presynaptic
terminals release the inhibitory neurotransmitter “gamma amino butyric
acid: GABA”.
* Release of GABA ----> opening Cl- channels in the presynaptic terminal
------> ↑Cl- influx -----> neutralization of the excitatory effect of Na+
influx occurred when an action potential arrives the presynaptic terminal -
----> ↓ amplitude of the action potential ------> ↓opening of voltage - gated
Ca++ channels -----> ↓ Ca++ influx ----> ↓ release of the transmitter ----->
↓postsynaptic response.
Significance:
* Presynaptic inhibition occurs in many sensory pathways in the nervous
system.
* It is involved in:
1) The process of lateral inhibition in which the more strongly stimulated
neurons inhibit the less stimulated surrounding neurons. This minimizes
the sideways spread of signals in the sensory tracts and focuses on the
most important ones.
2) The pain control system in which presynaptic inhibition blocks
transmission of pain signals along the central pathways of pain.
Termination of synaptic transmission:
- This occurs when the neurotransmitter is removed from the synaptic cleft.
- This is done by one or more of the following ways:i) Re-uptake of the transmitter into the presynaptic terminal by an active
transport mechanism, specific for each transmitter.
ii) By enzymatic degradation within the cleft
itself . Some of the
breakdown products are then transported back into the presynaptic terminal.
iii) By diffusion of the transmitter out of the synaptic cleft into the
surrounding interstitial fluid.
General Properties of Chemical Synaptic Transmission
1- One – Way Conduction:
 This is known as “Bell- Magendie law”.
 At synapses, conduction of impulses occurs in one direction only; from
the presynaptic to the postsynaptic neurons & not in the opposite
direction.
Mechanism:
 The backward impulse produces no effect because there are no
transmitter vesicles in the presynaptic neuron.
2- Synaptic Delay:
 Definition: It is time passed between arrival of an action potential to the
synaptic knob and the occurrence of response in the postsynaptic neuron.
 This represents the time required for:
a) Release and diffusion of the neurotransmitter
b) Binding of the transmitter to the postsynaptic receptors.
c) Generation of PSPs & its summation to generate action potential.
 The minimum time for synaptic delay is about 0.5 millisecond.
 Significance:
can be used to determine the number of synapses present in a polysynaptic
reflex.
3- Synaptic Fatigue:
 Definition: It is progressive decline in rate of discharge of the
postsynaptic neuron, following rapid strong stimulation of the presynaptic
neuron.
 Mechanism: Depletion of the stores of the neurotransmitter in the
synaptic knobs, because there is no enough time resynthesis and reuptake
mechanisms that refill the stores under intensive stimulation. Synaptic
fatigue disappears when the transmitter has been replenished.
 Hypoxia accelerate synaptic fatigue while strychnine delays it.
 In sever conditions, synaptic transmission completely stops. This is called
"synaptic block".
 Significance: Synaptic fatigue when occurs protects CNS from
overexcitability (a protective mechanism).
4- POST-TETANIC FACILITATION (POTENTIATION)
 When a presynaptic terminal is stimulated rapidly for a period of time,
the synapse becomes more responsive to subsequent stimuli than normal
for a period of seconds or minutes.
 This is called “Post-Tetanic Facilitation or Potentiation”.
 It is related to the excess rise of Ca2+ inside the synaptic knob (due to
delay in Ca2+ extruding mechanism outside the knob). The elevated Ca2+
inside the knob causes more and more vesicles to release their transmitter,
producing a greater response of the post synaptic neuron.
 The physiological significance of the post-tetanic facilitation may
have a role in the memory process in C.N.S.
5- Long - Term Potentiation:
 Brief rapid repeated stimulation of presynaptic terminal -----> prolonged
↑in rate of postsynaptic discharge.
 Mechanism: It is initiated mainly by an increase of the intracellular Ca2+
concentration in the postsynaptic neuron rather than the presynaptic knob
through opening of certain Ca2+ channels in the postsynaptic membrane .
 Significance: It occurs in some parts of the nervous system , but it has a
special significance in the hippocampus; which plays an important role in
learning and memory.
6- Effect of Hypoxia on Synaptic Transmission:
 Hypoxia ↓neuronal excitability & synaptic transmission.
 This is due to the need of the neurons for adequate oxygen supply.
 interruption of cerebral circulation for about 7 seconds causes loss of
consciousness (coma) & for about 2-3 minutes causes irreversible damage
of the brain.
7- Effects of pH on Synaptic Transmission:
 In brain synapses, alkalosis ↑ excitability and synaptic transmission
while acidosis ↓it.
 So, ↑pH to 7.8 to 8.0,
produces severe convulsions whereas, ↓pH
around 7.0 produces coma. This latter condition is always seen in severe
uremic or diabetic acidosis .
7- Effect of Drugs on Synaptic Transmission:
Drugs ↑ing neuronal excitability
Drugs ↓ ing neuronal excitability
& synaptic transmission
& synaptic transmission
1- Caffeine (found in coffee) and 1- Volatile anesthetics:
theophylline (found in tea ):
↑ threshold needed for excitation of
↓threshold needed for excitation of the the postsynaptic neuron.
postsynaptic neuron.
2- Strychnine:
2- Tranquilizers:
inhibits the action of glycine (an ↑Clinhibitory neurotransmitter) on
neurons.
influx
---->
inhibition
of
the postsynaptic neurons at specific regions
in the nervous system.
NEUROTRANSMITTERS
 Neurotransmitters of the central nervous system
can be broadly classified into two groups:
(i) Small- molecule neurotransmitters.
(ii) Neuropeptides
Class I
Acetylcholine
Class II
Biogenic Amines
Dopamine
Norepinephrine
Serotonin
Small - Molecule Neurotransmitters
 rapidly acting
cause most of the fast responses of the nervous
system, such as transmission of sensory impulses
to the brain and motor signals to the muscles.
 synthesized in the presynaptic terminals
 stored there in the transmitter vesicles untill
released during the process of synaptic
transmission to act on the postsynaptic membrane
receptors
Histamine
Class III
Amino Acids
Glutamate
Aspartate
γ- Aminobutyric acid
(GABA)
Glycine
Class IV
Nitric oxide (NO)
Carbon monoxide (CO)
Neuropeptides
 several families of peptides that posses relatively high molecular weight
whose actions are usually slow and prolonged
 synthesized in the soma of neurons where they are stored within secretory
vesicles that are then transported to the nerve terminals by the mechanism of
“axonal streaming” of the axon cytoplasm.
 Act through G-protein coupled receptors -----> long-term effects in the post-
synaptic neurons as:
1.
metabolic changes in the cell.
2.
activation or deactivation of specific genes.
3.
Prolonged alterations in the numbers of excitatory or inhibitory receptors in
the postsynaptic membrane.
 Some of these effects can last for days or perhaps even months or years.
 Examples: Angiotensin, substance-P, neuropeptide-Y, calcitonin-gene related
peptide, soamtostatin, opioid peptides.