Aspects of Neuroscience

BCHE4040/LSCI5440

Synapses
Prof Kwok Fai LAU
School of Life Sciences
2023-24
CUHK 1
Neurons
• Over 80 billion neurons in a human brain
• Neurons specialize for intercellular communication

Typical structure of a neuron

• Extensive projections/branching → axons and dendrites

• Neurons are the basic units for the formation of neural network

2
Neural Circuit
• is a population of interconnected neurons to carry out a
specific function when activated.
• e.g. Myotatic reflex (Knee-jerk response)
Sensory neurons - Carry information from periphery toward
brain/spinal cord
Muscle sensory receptor
- stimulate (1) motor neurons to
Extensor muscle extensor muscle
(2) interneurons

Flexor
muscle
Motor neurons - Carry Interneurons – inhibit motor neurons
information away from to flexor muscle
brain/spinal cord

Figure 1.7
Neuroscience 5th Ed
©2012 Sinauer Associates 3
Neurons
• Synapse – a contact made by axon ending to another neuron or
to the target effector cell ( for signal communication)

Aging : theories and potential therapies

© 2005 by Joseph Panno, PhD. Facts On File 4
Synapses
• A synapse is a structure that permits a neuron to pass an
electrical or chemical signal to another cell
• Two different types : (1) electrical (2) chemical

Figure 11.1
From Neuron to Brain 5th Ed
©2012 Sinauer Associates

• Chemical transmission is the prevalent mode of synaptic

transmission
5
 Structure of Electrical Synapses

Connexons

Connexin

Connexon - is an assembly of six proteins called connexins

that form the channel for a gap junction between the Figure 5.1
cytoplasm of two adjacent cells. Neuroscience 5th Ed 6
©2012 Sinauer Associates
• Electrical transmission is used at certain invertebrate and
vertebrate synapses specialized for very fast responses

7
 Electrical synaptic transmission in the giant motor
synapse of crayfish
• An electrical synapse between the neurons in the
abdominal nerve cord of crayfish that mediates
crayfish escape reflex

• A current flow in presynaptic lateral giant axon

that caused the depolarization of postsynaptic
motor neuron immediately.
8
 Crayfish electrical synapses
• Rapid transmission of signals → essentially no time delay
Crayfish electrical synapse Chemical synapse

About 1 ms
synaptic delay
Figure 5.2
Neuroscience 5th Ed
©2012 Sinauer Associates

Time (ms)
• reducing the time between the presence a threatening stimulus
and a potentially life saving motor response
9
• Electrical synapses allow synchronization of electrical
activity among populations of neurons/cells (economical)
e.g. Electrical transmission between the Two neurons connected by electrical synapse
hormone-secreting neurons within
hypothalamus,

➢ ensures all cells fire action potentials at

about the same time
➢ release the hormone at the same time

A similar example
Heart cells are connected via gap junctions
➢ synchronization of action potential firing
➢ all heart cells work together simultaneously Figure 5.2
Neuroscience 5th Ed
©2012 Sinauer Associates
to coordinate cardiac muscle contraction 10
Advantages of electrical synapses
• Greater speed – rapid reflex action
• All cells in a group work simultaneously (synchronization of
electrical activity)

• Connexons have quite wide pores – intercellular transfer of key

molecules (e.g. calcium, ATP etc)

• More reliable than chemical synapses – transmission is less likely to be

disrupted by synaptic depression or blocked by neurotoxins

Disadvantages of electrical synapses

• Do not have inhibitory effect
• Limited ability to be integrated with other inputs
• Short-term actions (no second messengers)
11
Chemical Synapses
Otto Loewi’s experiment to demonstrate chemical transmission (1921)

• He hypothesized that neurons release chemical

substances that influence the activity of the heart

Nobel Prize in Physiology or Medicine (1936)

electrically
stimulation of Discovered the role of acetylcholine as an
vagus nerve endogenous neurotransmitter

Chamber 1

Frog Heart 1

Figure 5.4
Chamber 2 Neuroscience 5th Ed
©2012 Sinauer Associates

Frog Heart 2
Vagus substance = acetylcholine

• Conclusion : electrically stimulation causes the vagus nerve to release chemicals

12
that decrease heart contractions.
Structure of Chemical Synapses

SNARE protein
complex

Figure 1 (Section C1)

BIOS Instant Notes Neuroscience
©2011 Garland Science

Active zone – the region for transmitter release; for docking of synaptic vesicles
(via SNARE proteins)

Synaptic cleft → 20-50nm in width

Postsynaptic density (PSD) – a macromolecular signaling assembly embedded in

the postsynaptic membrane to concentrate receptors in the synaptic cleft
13
• Chemical synapses are classified by where on the receiving
cell they are located

BioNinja

Axo-dendritic Axo-somatic Axo-axonic

synapse synapse synapse
(predominant)

14
Advantages of Chemical Transmission
• Unidirectional transmission (presynaptic to postsynaptic neurons →
information is transferred sequentially to different cells in a neural circuit)
• Produce both excitatory and inhibitory postsynaptic potentials
• Signal amplification for weak presynaptic signal
• Signal computation - combine excitatory and inhibitory signals received from
multiple presynaptic neurons→ allows the neuron to integrate information
from various sources EPSP – excitatory postsynaptic potential
IPSP – inhibitory postsynaptic potential

Figure 5.14 15
Neuroscience 5th Ed
©2012 Sinauer Associates
• Multiple receptors → differential actions for the same
neurotransmitter

e.g. Acetylcholine (Ach)

Cardiac muscle → muscarinic receptors → lower heart beat
(reduce muscle contraction)
Skeletal muscle → nicotinic receptors → induce muscle
contraction

• Multiple control points (alteration of synthesis, release and

recycle of neurotransmitters , and receptor levels)

16
Summary: Electrical synapse vs Chemical synapse

Figure 5.1
Neuroscience 3rd Ed 17
©2004 Sinauer Associates
 Neurotransmitters
• A neurotransmitter is defined as a chemical substance that is synthesized
in a neuron, released at a synapse following depolarization of the nerve
terminal which binds to receptors on the postsynaptic terminal to trigger a
specific response
• Over 100 different neurotransmitters have been identified

Table 8-1
Essential Neuroscience
©2006 Lippincott Williams & Wilkins 18
Criteria used for identifying neurotransmitters
1. The substance must be synthesized in the neuron (and the
enzymes needed for its synthesis must be present in the
neuron)
2. The substance must be released in response to presynaptic
depolarization and the release must be Ca2+ -dependent
3. Specific receptors for the substance must be present on
the postsynaptic cell

Box 5A
Neuroscience 5th Ed 19
©2012 Sinauer Associates
 Synthesis and release of neurotransmitters
Small-molecule transmitter Peptide transmitter
1. Synthesis of
1. Synthesis of neurotransmitter
enzymes in cell body precursors and
enzymes in cell
body

2. Axonal transport
of precursors and
2. Axonal transport enzymes
of enzymes
5. Transport of
precursor
into terminal 4. Neurotransmitter 3. Enzymes modify
diffuses away and precursors to
3. Synthesis and degraded by
packaging of produce peptide
proteolytic enzymes transmitter
4. Release of
neurotransmitter
neuro-
transmitter

Figure 5.5 20
Neuroscience 5th Ed
©2012 Sinauer Associates
Criteria used for identifying neurotransmitters
1. The substance must be synthesized in the neuron (and the
enzymes needed for its synthesis must be present in the
neuron)
2. The substance must be released in response to presynaptic
depolarization and the release must be Ca2+ -dependent
3. Specific receptors for the substance must be present on
the postsynaptic cell

Box 5A
Neuroscience 5th Ed 21
©2012 Sinauer Associates
Neurotransmitter release
• occurs by calcium-dependent exocytosis from vesicles, in response
to excitation of the axon terminal by action potentials

1. Experiment to show entry of Ca2+ through presynaptic

voltage-gated calcium channels causes transmitter release

A large synapse in
squid

22
Indicates release of neurotransmitter
2. Experiment to show that a rise in presynaptic Ca2+ conc.
triggers transmitter release from presynaptic terminals

(1) (2)

1. Presynaptic injection of Ca2+ into squid giant nerve

2. Presynaptic injection of Ca2+ and Ca2+ chelator into
squid giant nerve

Figure 5.11
Neuroscience 5th Ed
©2012 Sinauer Associates

Indicates release of
neurotransmitter 23
• Two types of vesicles
Small clear synaptic vesicles (SSVs);
small clear core vesicles
• 40-60nm in diameter

Large dense-core vesicles (LDCVs)

• They are electron-dense in electron
Figure 2 (Section C1)
BIOS Instant Notes Neuroscience
micrographs
©2011 Garland Science
• 90-250nm in diameter

Small molecule Peptide transmitter

transmitter Figure 5.12
Neuroscience 5th Ed
©2012 Sinauer Associates
24
(1) Small clear synaptic vesicles (SSVs)
• Typically pre-docked to the plasma membrane (active zone) in
advance of Ca2+ entry
• The mechanism for SSV release has a lower affinity to calcium
→ require high [Ca2+] to trigger release (half-maximal release [Ca2+]
=100 to 200µM)
• Arrival of action potential → influx of calcium restricted to a small
region (local conc. reaches 200M)

pre-docked SSVs
25
(2) Large dense-core vesicles (LDCVs)
• Are situated away from the active zone
• released by high-frequency stimulation
• only small amount of calcium
manages to diffuse to the LDCVs

→ The mechanism for LDCV

release has a higher
affinity to calcium

→ half-maximal release
[Ca2+]=0.4µM
• Cause a delay in release (about 50ms)
26
 Synaptic Vesicle Cycling

The vesicle trafficking cycle Molecular organization of a

synaptic vesicle
1.Transmitter loading 8. Uncoating

2. Mobilization 7. Budding

3. Docking 6. Coating

4. Priming NT release

5. Fusion

Figure 5.13
Neuroscience 5th Ed
©2012 Sinauer Associates

27
Vesicle fusion

Synaptotagmin

Synaptobrevin

SNAP-25

Syntaxin

Figure 5.14
Neuroscience 5th Ed
©2012 Sinauer Associates

SNARE = Soluble NSF (N-ethylmaleimide-sensitive factor)

Attachment Protein REceptor 28
Botulism (肉毒桿菌中毒)
• Botulinum toxins (BoTXs), produced by the bacteria Clostridium botulinum, causes
food poisoning
• affect neuromuscular transmission causes skeletal weakness, in extreme cases
respiratory failure
• BoTXs are highly specific proteases that inhibit neurotransmitter release by
cleaving the SNARE proteins

Bai et al. Medicine (Baltimore)2018 Aug;97(34):e10659.

29
Uses of Botulinum Toxin Type A (BTX-A)
(1) Treatment of Upper motor neuron syndrome (UMNS)
• muscles with an impaired ability to effectively lengthen due
to their over-activeness
• BTX-A decreases the over-active muscle level of contraction

(2) BTX-A (BOTOX®) to treat wrinkles

• Wrinkles are caused by muscular contractions
• Injection of BTX-A has beneficial effects on wrinkles

From www.calla-aesthetics.co.uk 30
Botulism (肉毒桿菌中毒) cases

31
 Molecular mechanisms of endocytosis following
neurotransmitter release

Figure 5.15B
Neuroscience 5th Ed
©2012 Sinauer Associates

Requires Ca2+ Auxilin – a co-factor to

recruit Hsc-70
Hsc-70 – an ATPase to
remove the clathrin coat

32
Vesicle refilling
1. Acidification by an
2. Efflux of H+ → energy
ATPase

3. Active transport of
neurotransmitter

33
Sequence of events involved in transmission
at a typical chemical synapse

Figure 5.3
Neuroscience 5th Ed 34
©2012 Sinauer Associates
Criteria used for identifying neurotransmitters
1. The substance must be synthesized in the neuron (and the
enzymes needed for its synthesis must be present in the
neuron)
2. The substance must be released in response to presynaptic
depolarization and the release must be Ca2+ -dependent
3. Specific receptors for the substance must be present on
the postsynaptic cell

Box 5A
Neuroscience 5th Ed 35
©2012 Sinauer Associates
Neurotransmitter receptors
Two subfamilies
1. Ligand-gated ion channels (ionotropic receptors)
• Consist of multimeric proteins
• Each subunit spans the plasma membrane and
contributes to the formation of the pore of the ion
channel
• They combine transmitter-binding and channel
function into one molecular entity → direct and fast
transmission

36
2. G-protein-coupled receptors
• Largest group of metabotropic receptors (modulate
metabolic activities)
• Do not have the ion channel as part of the receptor
• The opening/closing of the ion channels associated
with these receptors involves activation of
intermediate molecules call G-proteins → Indirect
transmission

Activation
of
G-protein

Figure 12.1
From Neuron to Brain 5th Ed
©2012 Sinauer Associates

37
Table 8-3
Essential Neuroscience
©2006 Lippincott Williams & Wilkins

38
Sequence of events involved in transmission
at a typical chemical synapse
Neurotransmitter
synthesis

Neurotransmitter
packaging
Membrane
Recycling

Neurotransmitter
release

Termination of
neurotransmitter
Receptor
action
binding

39
Termination of neurotransmitter action
• Allows new signals to propagate → update on recent
changes in incoming signals

• Prevents desensitization (the transmitter-gated channels

remain closed even in the presence of transmitter )

(1) Enzymatic destruction in the synaptic cleft

e.g. Acetylcholine is degraded by
acetylcholine esterase

40
(2) Diffuse away from the synaptic cleft (and may be followed
by re-uptaking through specific neurotransmitter
transporter located in the presynaptic membrane)
(3) Transport by specific transporters

Figure 1 (Section C4) Figure 2 (Section C4)

BIOS Instant Notes Neuroscience BIOS Instant Notes Neuroscience
©2011 Garland Science ©2011 Garland Science

Na+/K+ - cotransporter Na+/Cl- - cotransporter

Glutamate GABA; glycine;

norepinephrine/epinephrine;
dopamine; serotonin; choline
41
(4) Retrograde signaling with endocannabinoids
• Endocannabinoids – endogenous small lipid molecules
that interact with canabinoid receptors
• Two known endocannabinoids

Arachidonic acid + ethanolamine Arachidonic acid + glycerol

• A feedback mechanism to regulate conventional forms

of synaptic transmission (best documented action →
GABA release)
42
 6
1. Depolarization
7 2. Open of voltage-gated calcium channel
3. Influx of Ca2+
4. Ca2+ stimulates the synthesis of
endocannabinoids
2 5. Diffuse across the postsynaptic
5 membrane
6. Bind to CB1 receptor (G-protein
1 coupled receptor) on the
3 presynaptic membrane
4 Figure 12.18
From Neuron to Brain 5th Ed
©2012 Sinauer Associates
7. Reduce the opening of presynaptic
calcium channels
PIP2 = phosphatidylinositol-4’ 5’-bisphosphate
PLCb1 = phospholipase C b1
DAG = diacylglycerol
DAGL = diacylglycerol lipase
→ Communicate between “Post” to “Pre”

Are endocannabinoids neurotransmitters? 43