Interneuronal Communication

The Synapse

AMER H. RAHHAL, MD, PhD

The Synapse
Objectives

➢Synapse definition.
➢Functions of synapses.
➢Structure of synapses.
➢Types of synapses: anatomical & functional.
➢Synaptic transmission & neurotransmitters.
➢Fate of neurotransmitters.
➢Electrical events at synapses (EPSPs & IPSPs).
➢Properties of synaptic transmission.
➢Factors affecting synaptic transmission.
The Synapse
Overview

➢ The human brain is made up of approximately 86 billion neurons.

➢ Children have roughly 1016 synapses.

➢ Adults have somewhere from 1-5  1015 synapses.

How these neurons communicate to each other?

➢ They “ Talk ” to each other using a combination of Electrical and

Chemical signals.
The Synapse
Definition

➢ A Space between adjacent neurons. i.e. the places where neurons connect and
communicate with each other.

➢ It is not anatomical continuation. But, it is only a physiological continuity between

cells.

➢ Relays information from neuron to target cell.

Neuro-synapse
✓ Neuron ➔ Neuron

✓ Neuron ➔ Muscle
Neuromuscular synapse
✓ Neuron ➔ Gland

Neuroglandular synapse
The Synapse
Function
What happens at the synapse?

➢ Synaptic transmission is a complex process that permits

grading and adjustment of neural activity necessary for
normal function.
➢ Information is transmitted in the CNS mainly in the form
of APs “Nerve impulse”, which pass from one neuron to
another cell.
➢ Each impulse from its way from one neuron to another
may:-
➢ Be blocked in its transmission from one neuron to another.
➢ Be changed from single impulse to repetitive impulses.
The Synapse
Structure
➢ Presynaptic ending: portion of the axon
conveying information to the next cell.
➢ Synapse or synaptic cleft: the space
between neurons where communication
occurs. It is filled with extracellular fluid and
spans an area of approximately 20 nm.
➢ Postsynaptic membrane: the portion of the
neuron (usually dendrite) that receives
information.
➢ Presynaptic and postsynaptic receptors:
proteins in both the presynaptic and
postsynaptic ending that allow for
information to be transferred.
The Synapse
Structure

➢ Synaptic vesicles: small enclosed membranes

found in presynaptic ending that contain
neurotransmitter.

➢ Neurotransmitter: substance in vesicles that

are released in synapse and convey info to
the next cell.
The Synapse
Classification

➢Synapse is classified into three classes:

✓ Anatomical classification.

✓ Functional classification.

✓ On the basis of their functions.

The Synapse
Anatomical Classification

➢ Based on the parts of the neurons that participate in formation

of synapse and the direction in which the transmission of nerve
impulse occurs, they classify into:
✓ Axo-dendritic: synapses between the axon of one neuron and the
dendrite of another.
✓ Axo-somatic: synapses between the axon of one neuron and the
soma of another.
✓ Axo-axonic. (axon to axon)
✓ Dendro-dendritic. (dendrite to dendrite)
✓ Dendro-somatic. (dendrites to soma)
✓ Dendro-axonic. (dendrites to axon)
The Synapse
Functional Classification

➢The way in which information is

transferred between neuron and
neighboring cells is classified into:
➢ Electrical synapses.

➢ Chemical synapses.

➢?
The Synapse
Electrical synapses

➢ Membranes of the pre- and post-synaptic

neurons fuse together that form gap
junctions.

➢ Are less common than chemical synapses.

➢ Rare in CNS or PNS.

➢ Are important in the CNS in:

✓ Arousal from sleep.
✓ Mental attention.
✓ Emotions and memory.

✓ Ion and water homeostasis.

The Synapse
Electrical synapses

➢ The function of gap junction is to

allow local current to flow between
adjacent cells.

➢ Connexons: protein tubes in cell

membrane.

➢ Each connexon is comprised of six

identical subunits (connexins)

➢ Permeability of junction mediated

by conformation of the connexons.
The Synapse
Electrical synapses

➢ Action potential of one cell causes action potential in

next cell, almost as if the tissue were one cell.

➢ Important where contractile activity among a group of

cells important.

➢ Transmission of signals across electrical synapses is rapid.

➢ This involves movement of ions via gap junctions.

➢ Used when rapid conduction of signals is essential or to

synchronize cells.

➢ Found in cardiac and smooth muscles.

➢ Rare and occurs mainly in CNS, glial cells, and non

excitable cells that use electric signals like β-cells in
pancreas.
The Synapse
Chemical Synapses
➢ It is a specialized junction that transfers nerve impulse information
from a presynaptic membrane to a postsynaptic membrane using
Neurotransmitters (NTs).

➢ NTs give the nerve signal more specificity.

➢ NTs also control the operation of the nervous system by inhibition or

excitation or by modify its sensitivity.

➢ NTs are synthesized and stored in the presynaptic membrane.

➢ Electrical signal is converted into a neurocrine signal that crosses the

synaptic cleft and binds to a receptor on its target cell.

➢ The postsynaptic endings contains receptors for those NTs.

➢ The vast majority of synapses in NS are of chemical type.

The Synapse
On the basis of their functions

➢ Synapses are divided into two types:

➢ Excitatory synapses: transmit the impulses (Excitatory

function)

➢ Excitatory Postsynaptic Potential (EPSP)

➢ Is the non propagated electrical potential that develops
during the process of synaptic transmission.

➢ Inhibitory synapses: inhibit the transmission of impulses

(Inhibitory function)

➢ Inhibitory Postsynaptic Potential (IPSP)

➢ Is the type of synaptic inhibition that occurs due to the
release of an inhibitory NTs from post synaptic terminal
instead of an excitatory NTs. It is also called direct
inhibition.
The Synapse
Transmission of an Action Potential across Synapse

➢ Signals are transmitted across an electric

synapse within a few microseconds because
ions flow directly from the presynaptic cell to
the postsynaptic cell through gap junctions.
➢ Signal transmission across a chemical synapse is
delayed about 0.5 ms.
✓ The time required for secretion and
diffusion of neurotransmitter and the
response of the postsynaptic cell to it.
The Synapse
Synaptic transmission & neurotransmitters
 The Synapse
Basic Function of Chemical Synapse
➢ Nerve impulse arrives at presynaptic terminal.

➢ Depolarization causes voltage-gated Ca+² channels to open.

➢ Increases Ca+² influx, get a transient elevation of internal Ca+² ~100 mM.

➢ Vesicle exocytosis.
➢ Increase in Ca+² induces fusion of synaptic vesicles contain
neurotransmitters to membrane.

➢ Vesicle fusion to membrane releases stored neurotransmitter.

➢ Transmitter diffuses across cleft to postsynaptic side.

The Synapse
Basic Function of Chemical Synapse

➢ Neurotransmitters bind to receptor either:

i. Ligand-gated ion channel.

ii. Receptors linked to 2nd messenger systems.

➢ Binding results in a conductance change

i. Channels open or close.

ii. Binding results in modulation of postsynaptic side.

➢ Postsynaptic response
➢ Change in membrane potential (e.g. muscle contraction
in the case of a motor neuron at a neuromuscular
junction.

➢ Neurotransmitter is removed from the cleft.

The Synapse
Fate of neurotransmitters

➢ Broken down by enzymes.

✓ Acetylcholine esterase breaks down acetylcholine in the synaptic cleft.
✓ Many nerve gases and insecticides work by blocking acetylcholine
esterase.
✓ Prolongs synaptic communication.

➢ Recycled by uptake.
✓ Most neurotransmitters are removed by Na+/NT symporters.
✓ Due to a specific neurotransmitter transporter
✓ Recycled by uptake into presynaptic terminal or other cells e.g.(glial
cells will take up neurotransmitters).

➢ Diffusion, simple diffusion away from site.

The Synapse
Fate of neurotransmitters
1 Neurotransmitters can be returned
to axon terminals for reuse or
transported into glial cells.

2 Enzymes inactivate
neurotransmitters. Blood
vessel
3 Neurotransmitters can diffuse Axon terminal of
out of the synaptic cleft. presynaptic cell

Synaptic
vesicle 3

Glial cell

Enzyme
Postsynaptic cell 2
The Synapse
Types of neurotransmitters

➢There are three main categories of neurotransmitters:

➢ Small molecules used for fast action information transmission.
✓ Excitatory → Glutamate, receptors are AMPA, NMDA, kainate, mGluR
✓ Inhibitory → GABA, receptors are “GABA”

➢ Small molecules used for slower modulation of network activity.

✓ Dopamine → behavior, learning, receptors are “D”
✓ Serotonin → mood, receptors are “5-HT”
✓ Acetylcholine (ACh) → attention, receptors are “M” and nicotinic
✓ Norepinephrine (NE) → vigilance, receptors are alpha, beta
✓ Histamine (HIST) → sleep/wake, receptors are “H”
✓ Epinephrine/adrenalin (EP/AD) → receptors are alpha, beta
✓ Melotonin (MEL) → circadian rhythm, receptors are “M”
✓ Adenosine → receptors are “A” (caffeine affects these)
✓ Nitric oxide (NO)
✓ Glycine → inhibitory, receptors are “Gly”, used only in spinal cord
The Synapse
Types of neurotransmitters

➢ Peptides (large protein molecules) used for slower modulation of

circuit function.
✓ Endorphins (enkephalin, dynorphin) → receptors are mu, sigma,
and kappa (morphine, codeine, heroine, etc. affect these)

✓ Cannabinoids → receptors are “CB” (marijuana affects these)

✓ Oxytocin → the “love” neurotransmitter (pair-bonding)

✓ Orexin / hypocretin → regulation of sleep/wake cycle, receptors are

“OX”, (dysfunction causes narcolepsy)

✓ Corticotropin releasing factor (CRF) → regulation of stress response

The Synapse
Synthesis and Recycling of Acetylcholine at a Synapse

Mitochondrion
Axon
terminal Acetyl CoA CoA

Enzyme Acetylcholine
1 1 Acetylcholine (ACh) is made
Synaptic from choline and acetyl CoA.
vesicle

2 In the synaptic cleft ACh is rapidly

3 broken down by the enzyme
acetylcholinesterase.

Choline Cholinergic
2
receptor 3 Choline is transported back into
the axon terminal and is used
to make more ACh.
Acetate Acetylcholinesterase (AChE) Postsynaptic
cell
The Synapse
Neurotransmitter Receptors

➢ NTs must be present and released.

➢ NTs must bind to specific receptor proteins in the postsynaptic

membrane.
Master Key
➢ Binding causes a conformational change in the receptor.

➢ A change in structure equals a change in function.

➢ Two major categories of receptors:

✓ Transmitter (ligand) gated ion channels.
✓ G-protein Coupled Receptors. (GPCR)

➔ NT represents a key.
➔ Receptor represents the Lock.
The Synapse
Postsynaptic Response

➢Ligand-gated Ion Channels

➢ Channel protein with a ligand binding domain.
➢ NT binding causes channel to open.
➢ Consequence depends on the specific ions that pass through
the pore.
➢ Na+ and K+ channels cause depolarization and are excitatory.
➢ Clˉ channels cause hyperpolarization and are inhibitory.

➢ Activation is generally rapid and is mediated by amino acids

and amines.
The Synapse
Postsynaptic Response
Excitatory Postsynaptic Potential (EPSP)

➢ An impulse arriving in the presynaptic terminal

causes the release of NT.
➢ The molecules bind to gated ion channels in the
postsynaptic membrane ➔ Influx of Na+ to the
postsynaptic cell causing the membrane to
depolarize.
➢ The resulting change in membrane potential in
the cell is known as EPSP.
➢ Excitatory Neurotransmitters
✓ ACh and glutamate.
The Synapse
Postsynaptic Response
Inhibitory Postsynaptic Potential (IPSP)

➢ An impulse arriving in the presynaptic terminal

causes the release of NT.
➢ The molecules bind to gated ion channels in the
postsynaptic membrane ➔ Influx of Cl- to the
postsynaptic cell causing the membrane to
hyperpolarize.
➢ The resulting change in membrane potential in
the cell is known as IPSP.
➢ Inhibitory Neurotransmitters
✓ Glycine and GABA
The Synapse
Postsynaptic Response
➢ G Protein-Coupled Receptors
➢ Receptor protein with a ligand binding domain and connected to
G–protein consisting of an alpha, beta and gamma subunit.
➢ When be Activated:
✓ Ligand binds to receptor.
✓ Receptor activates G-protein.
✓ G-protein dissociated.
✓ Alpha subunit activates an effector protein.

➢ G-proteins act in one of two ways:

✓ By opening ion channels.
✓ By activating enzymes that synthesize second-messenger molecules.

➢ Tend to be slower, longer lasting and have greater diversity than

ligand gated ion channels.
➢ Ligand may bind to a family of receptors with different effects due to
specific receptor type.
The Synapse
Postsynaptic Response
The Synapse
Synaptic properties

➢One-way conduction.
➢Synaptic delay.
➢Synaptic inhibition.
➢Summation.
➢Convergence and divergence.
➢Occlusion.
➢Fatigue.
➢Long-term potentiation.
➢Long-term depression
The Synapse
Synaptic properties

➢One-way conduction
➢ Synapses generally permit conduction of impulses in one-
way i.e. from pre-synaptic to post-synaptic neuron.
The Synapse
Synaptic properties

➢Synaptic delay
➢ Is the minimum time required for transmission across the synapse.

➢ This time is taken by:

✓ Discharge of transmitter substance by pre-synaptic terminal.

✓ Diffusion of transmitter to post-synaptic membrane.

✓ Action of transmitter on its receptor.

✓ Action of transmitter to ↑ membrane permeability.

✓ Increased diffusion of Na+ to ↑ post-synaptic potential.

The Synapse
Synaptic properties

➢Synaptic inhibition
➢ Types:
I. Direct inhibition.

II. Indirect inhibition.

III. Reciprocal inhibition.

IV. Inhibitory interneuron.

V. Feed forward inhibition.

VI. Lateral inhibition.

The Synapse
Synaptic properties

I. Direct inhibition
❖Post-synaptic inhibition, e.g. some interneurons in spinal cord that
inhibit antagonist muscles. Neurotransmitter secreted is Glycine.

❖Occurs when an inhibitory neuron (releasing inhibitory substance) act

on a post-synaptic neuron leading to ➔ its hyperpolarization due to
opening of Cl¯ [IPSPs] and/or K+ channels.
The Synapse
Synaptic properties

II. Indirect inhibition

✓ Presynaptic inhibition.
❖ This happens when an inhibitory synaptic knob lie directly on
the termination of pre-synaptic excitatory fiber.

❖ The inhibitory synaptic knob release a transmitter which

inhibits the release of excitatory transmitter from the pre-
synaptic fiber.

❖ The transmitter released at the inhibitory knob is GABA.

❖ The inhibition is produced by ↑ Cl¯ and ↑ K+. e.g. occurs in

dorsal horn ➔ pain gating.
The Synapse
Synaptic properties

III. Reciprocal inhibition

➢ Inhibition of antagonist activity is initiated in the
spindle in the agonist muscle.
✓ Impulses pass directly to the motor neurons supplying
the same muscle and via branches to inhibitory
interneurons that end on motor neurons of antagonist
muscle.
The Synapse
Synaptic properties

IV. Inhibitory interneuron (Renshaw cells)

➢ Negative feedback inhibitory interneuron of a spinal
motor neuron .

➢ This feedback inhibition also occurs in:

➢ Cerebral cortex.

➢ Limbic system.

➢ Note that Renshaw cells are in spinal cord.

The Synapse
Synaptic properties

V. Feed forward inhibition

➢ occurs in the cerebellum to limit the duration of excitation.

VI. Lateral inhibition

➢ Because of lateral inhibition, the lateral pathways are
inhibited more strongly.

➢ This happens in pathways utilizing most accurate

localization. e.g. movement of skin hairs can be well
located, temperature and pain are poorly located.
The Synapse
Synaptic properties
➢Summation
➢ The addition of post synaptic potential.
➢ There are two types:
➢ Spatial summation. (space)
➢ The adding together of EPSPs generated simultaneously at many different synapses on a dendrite.
➢ Two or more presynaptic inputs are active at the same time.
➢ A space (spatial) dependent process.
➢ Occurs in a Convergent Synapse.

➢ Temporal summation. (time)

➢ The adding together of EPSPs generated at the same synapse if they occur in rapid succession,
within 1-15 msec. of one another.

➢ The same presynaptic fiber fires AP in quick succession.

➢ A Time (Temporal) dependent process.

➢ Occurs in a Divergent Synapse.

The Synapse
Spatial Summation
Presynaptic
axon terminal
1 Three excitatory neurons
fire. Their graded potentials
1 separately are all below
threshold.

Trigger zone

Action
potential
The Synapse
Spatial Summation
Presynaptic
axon terminal
1 Three excitatory neurons
fire. Their graded potentials
1 separately are all below
threshold.

2 Graded potentials arrive at

trigger zone together and sum
to create a suprathreshold
signal.

Trigger zone

Action
potential
The Synapse
Spatial Summation
Presynaptic
axon terminal
1 Three excitatory neurons
fire. Their graded potentials
1 separately are all below
threshold.

2 Graded potentials arrive at

trigger zone together and sum
to create a suprathreshold
signal.

3 An action potential is
2
generated.

Trigger zone
3

Action
potential
The Synapse
Spatial Summation

1 One inhibitory and two

excitatory neurons fire.

Inhibitory
neuron
1

Trigger zone

No
action potential
The Synapse
Spatial Summation

1 One inhibitory and two

excitatory neurons fire.

2 The summed potentials

Inhibitory are below threshold, so
neuron
1 no action potential is
generated.

2
Trigger zone

No
action potential
The Synapse
Temporal Summation
The Synapse
Temporal Summation
The Synapse
Synaptic properties

➢Convergence
➢ When many pre-synaptic neurons
converge on any single postsynaptic
neuron.

➢ Allows a neuron to receive input

from many neurons in a network.
The Synapse
Synaptic properties

➢The highly branched dendrites

of a Purkinje cell demonstrate
Convergence.
The Synapse
Synaptic properties

➢Divergence
➢ Axons of most pre-synaptic neurons
divide into many branches that
diverge to end on many post-
synaptic neuron.
➢ Allows one neuron to communicate
with many other neurons in a
network.
The Synapse
Synaptic properties
Axon terminals
of presynaptic
neurons Dendrite of
postsynaptic
neuron

➢ The abundance of synapses

on a postsynaptic neuron
demonstrate Divergence.

Glial cell
processes

Axon
The Synapse
Synaptic properties

➢Occlusion
➢ Decrease expected response due to pre-synaptic
fibers sharing post-synaptic neuron [overlap].

➢ Neuromodulation: non-synaptic action of a substance

on neurons that alters their sensitivity to synaptic
stimulation or inhibition. e.g. neuropeptides, steroids
The Synapse
Synaptic properties

➢Fatigue
➢ Exhaustion of neurotransmitter.
➢ If the pre synaptic neurons are continuously stimulated
there may be an exhaustion of the neurotransmitter.

➢ Resulting is stoppage of synaptic transmission.

➢ The post synaptic membrane become less sensitive to

the neurotransmitter.
The Synapse
Synaptic properties

➢Long-term potentiation
➢ Rapidly developing persistent enhancement of postsynaptic potential
response to presynaptic stimulation after brief period of rapidly
repeated stimulation of presynaptic neuron.
 The Synapse
Synaptic properties

➢ Mechanism used in learning and

memory using Glutaminergic
Receptors.
The Synapse
Synaptic properties

➢Long-term depression
➢ First noted in Hippocampus.
➢ Later shown Through brain.
➢ Opposite of Long-term potentiation.
➢ Decrease synaptic strength.
➢ Caused by slower of presynaptic neuron.
➢ Smaller rise of Ca+²
➢ Occurs in amino 3 hydroxy -5-methylisoxazole4-propionate
AMPA receptors.
The Synapse
Presynaptic Inhibition

Presynaptic inhibition
No neurotransmitter
Inhibitory neuron release
Target cell
3
Presynaptic
axon terminal No response

Excitatory
neuron 1 2
Response
Action potential
Neurotransmitter
released

Response

1 An excitatory neuron 2 An action potential 3 An inhibitory neuron fires, blocking

fires. is generated. neurotransmitter release at one synapse.
The Synapse
Postsynaptic Inhibition

Postsynaptic inhibition

Inhibitory neuron modulates the signal No response

IPSP
+ No response
EPSP
Excitatory
neuron

No response
1 One excitatory and one 2 Modulated signal in 3 No action potential
inhibitory presynaptic postsynaptic neuron initiated at trigger zone. 4 No response in
neuron fire. below threshold. any target cell.
The Synapse
Factors affecting synaptic transmission

WHAT ARE THE FACTORS EFFECTING SYNAPATIC TRANSMISSION?

The Synapse
Factors affecting synaptic transmission
ALKALOSIS
➢ Normally, alkalosis greatly increases neuronal
excitability.

➢ A rise in arterial blood pH from the 7.4 to 7.8 to 8.0 often

causes cerebral epileptic seizures because of increased
excitability of some or all of the cerebral neurons.

➢ This can be demonstrated especially well by asking a

person who is predisposed to epileptic seizures to over
breath.

➢ The over breathing blows off carbon dioxide and

therefore elevates the pH of the blood momentarily.
The Synapse
Factors affecting synaptic transmission

ACIDOSIS
➢ Conversely, acidosis greatly depresses neuronal
activity;

➢ A fall in pH from 7.4 to below 7.0 usually causes a

comatose state.

➢ In very severe diabetic or uremic acidosis, coma

virtually always develops.
The Synapse
Factors affecting synaptic transmission
DRUGS
➢ Many drugs are known to increase the excitability of
neurons, and others are known to decrease excitability. Caffeine

✓ Caffeine ➔ Coffee.

✓ Theophylline ➔ Tea.

✓ Theobromine ➔ Cocoa,

➢ All increase neuronal excitability, presumably by reducing Theophylline

the threshold for excitation of neurons.

Theobromine
The Synapse
Factors affecting synaptic transmission
DRUGS
➢ Strychnine is one of the best known of all agents that increase
excitability of neurons.

➢ It does not do this by reducing the threshold for excitation of

the neurons; instead, it inhibits the action of some normally
inhibitory transmitter substances, especially the inhibitory
effect of glycine in the spinal cord.

➢ The effects of the excitatory transmitters become Strychnine

overwhelming, and the neurons become so excited that they
go into rapidly repetitive discharge, resulting in severe tonic
muscle spasms.
The Synapse
Injury to Neurons

Site of injury

Proximal stump Distal stump

➢ If the cell body is not damaged

the neuron will most likely survive.
➢ Axon healing is similar to growth Axon Myelin

cone of a developing axon.

➢ Survival of neurons depend on
neurotrophic factors.