PHYSIOLOGY BLOCK 1

Lecture: 4 – Synapses and Synaptic Transmission Date: August 3, 2015

Lecturer: Dr. Arlene R. Ng, M.D., Ph.D. Trans Team: Diaz, Dino, Endaya

Topic Outline o With direct open fluid channels conducting electricity

from one cell to the next
I. Synapses and Synaptic Transmission
A. Definition of a Synapse o Pre- and postsynaptic membranes come close
B. Synaptic Transmission together forming gap junctions
II. Types of Synapses o Form low-resistance bridges through which ions
A. Electrical Synapse pass with relative ease from the interior of one cell
B. Chemical Synapse to the interior of the next
III. Principles on Chemical Transmission  Gap junctions and connexons
A. Neurotransmitters o Direct channels (connexon) are low-resistance
B. Presynaptic Cell Processes pathways
C. Synaptic Cleft Processes o Connexins (proteins) form connexons (which are
D. Postsynaptic Cell Processes porous at the junctions)
IV. Overall process
o Mediating agent: ionic current
V. Synaptic Delay
VI. Synaptic integration o Cells are electrically coupled
VII. Organization of Neural Pools o Responsible for ephaptic / electrotonic / electrical
VIII. Importance of Synapses transmission
o Almost instantaneous production of an action
potential in the post-synaptic neuron: responsible for
I. Synapses and Synaptic Transmission fast escape reflexes
o For highly synchronized activity in the brain
A. Definition of a Synapse
o Particularly common during early embryonic stages
 Junction where the axon or some other portion of one cell
(coordinated growth and maturation of neighboring
terminates on the dendrites, soma or axon of another
cells)
neuron or a muscle or gland cell
o Gap junctions are also found in
 Specialized site of contact - Glia
B. Synaptic Transmission - Epithelial cells
 Process of information transfer at synapses: may block - Smooth muscle cells
transmission, changed from a single impulse into repetitive - Cardiac muscle cells
impulses or may be integrated with impulses from other - Liver cells
neurons - Some glandular cells
 Complex process – excitatory or inhibitory (or sum of both) - Schwann cells (forming myelin sheath)
o Happens whether or not an action potential is generated  Wrapped around axons; almost devoid of
 Permits grading and adjustment of neural activity necessary cytoplasm
for normal functions  Mediate both intra- and intercellular
communication; also serve as nourishment for
II. Types of Synapses the axons beneath
 Passage of ions and metabolites across layers
Table 1. Distinguishing properties of Electrical and Chemical
Synapses. o Charcot-Marie-Tooth Disease (CMTX) [X
Type of Synapse Electrical Chemical Chromosome-linked form]
Synapse Synapse o Demyelination due to mutation in connexin32 gene
Distance between pre- 3.5nm 20-40nm o Prevents formation of functional gap junction
and postsynaptic cell channels essential for normal flow of metabolites in
membranes Schwann cells
Cytoplasmic continuity Yes No
B. Chemical Synapse
between pre- and
 The most prevalent synaptic transmission in the
postsynaptic cells
mature human nervous system
Ultrastructural Gap- Presynaptic
 The presynaptic cell contains an abundance of
components junction vesicles and mitochondria, microtubules, and synaptic vesicles
channels active zones;  The postsynaptic cell has corresponding receptors
postsynaptic  Secretes neurotransmitters that in turn acts on
receptors receptor proteins in the membrane of the next neuron
Agent of Transmission Ion current Chemical (may excite, inhibit or modify the second neuron)
transmitter  One-way conduction: from the presynaptic neuron to
Synaptic Delay Virtually Significant: at the post-synaptic neuron. Hence, signals are directed
absent least 0.3ms, at very specific goals
usually 1-5ms or
longer
Direction of transmission Usually Unidirectional
Bidirectional

A. Electrical Synapse

Figure 1. Electrical Synapse and Gap Junctions.

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 With synaptic cleft

 With synaptic delay
 Abundant
 Mediating agent: chemical messenger
 Responsible for chemical transmission

Figures 2 & 3. Anatomy of a Chemical Synapse.

 Anatomy of a Chemical Synapse

o Synaptic cleft – 20-40nm
 Filled with matrix of fibrous extracellular protein
(adhesion)
o Synaptic vesicles – 50nm
o Secretory granules – 100nm
 Contain secretory proteins
 Dense core vesicles (appear dark on EM)
o Membrane differentiations
 Dense accumulations of proteins adjacent to Figure 6. Comparison between Delay in Electrical and Chemical
Synapses.
and within membranes on either side of the
synaptic cleft
 Active zones III. Principles in Chemical Transmission
 Postsynaptic density A. Neurotransmitters
 Categories of CNS Synaptic membrane  Characteristics:
differentiations o Must be synthesized and stored in the presynaptic
o Gray’s Type I – Asymmetrical membrane terminal or neuron
differentiations = excitatory (enhanced signal to o Must be released upon stimulation
ensure exposure) o When experimentally applied, must produce a
o Gray’s Type II – Symmetrical membrane response in the postsynaptic cell that mimics the
differentiations = inhibitory response produced by release of neurotransmitter
from the presynaptic neuron
o Existence of removal mechanisms (for recycling) –
since not completely used up
 Disease: Myasthenia gravis - postsynaptic membrane
of neuromuscular junction has too few acetylcholine
receptors (ACh are degraded by cholinesterases)
o Treatment by introduction of anticholinesterase
drug to slow acetylcholine breakdown and allow
ACh to accumulate
 Around 50 discovered so far, more not yet elucidated
 Types:
1. Small-molecule, rapidly acting transmitters
a) Class I
i. Acetylcholine
b) Class II: The Amines
i. Norepinephrine
ii. Epinephrine
iii. Dopamine
iv. Serotonin
v. Histamine
Figure 4. Categories of CNS Synaptic Membrane Differentiation. c) Class III: Amino Acids
i. Gamma-aminobutyric acid (GABA)
 Common sites of synapses: axosomatic, axodendritic ii. Glycine
(spine and shaft) and axoaxonic iii. Glutamate
iv. Aspartate
d) Class IV
i. Nitric Oxide (NO)
2. Neuropeptides – slowly acting transmitters or
growth factors
- Has prolonged action and enacts long-term
changes (unlike small molecules)
- Synthesized as integral parts of large protein
molecules
- 1000 times more potent
a. Hypothalamic-releasing hormones
i. Thyrotropin-releasing hormone
ii. Luteinizing hormone-releasing hormone
iii. Somatostatin (growth hormone inhibitory
factor)

Figure 5. Common Synapse Sites. b. Pituitary peptides

i. Adrenocorticotropic hormone (ACTH)

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ii. β-endorphin o SNARE (SNAP Receptor; Soluble NSF Attachment

iii. α-melanocyte-stimulation hormone Protein Receptor) Proteins:
iv. Prolactin a. V-SNARE (vesicular SNARE)
v. Luteinizing hormone  Synaptobrevin (VAMP-vesicle
vi. Thyrotropin associated membrane protein
vii. Growth hormone Synaptotagmin
viii. Vasopressin b. T-SNARE (target membrane SNARE)
ix. Oxytocin  Syntaxin and SNAP-25
c. Peptides that act on gut and brain o Synaptotagmin
i. Leucine enkephalin
ii. Methionine enkephalin
iii. Substance P
iv. Gastrin
v. Cholecystokinin
vi. Vasoactive intestinal polypeptide (VIP)
vii. Nerve growth factor
viii. Brain-derived neurotropic factor
ix. Neurotensin
x. Insulin
xi. Glucagon
d. From other tissue
i. Angiotensin II
ii. Bradykinin
iii. Carnosine
iv. Sleep peptides
v. Calcitonin
B. Presynaptic cell: Processes Figure 8. Mechanism of Vesicular Proteins
 Synthesis of transmitters
o Manufacturing of chemical messengers  Mobilization, trafficking, docking of vesicles: Role of
o Synthesis located very near the terminals calcium and Rab3A protein
o Storage of transmitters in vesicles: Packaging of o Entry of Ca2+ into the nerve terminal leads to the
neurotransmitters into vesicles or granules opening of the fusion pore complex and
o Release of transmitters, and recycling of vesicles neurotransmitter release. Calcium entry also frees
o The chemiosmotic theory: requirement of energy for vesicles from the storage compartment through
transport of vesicles (since the act is against the phosphorylation of synapsins thus increasing the
concentration gradient availability of vesicles for docking at the presynaptic
 Storage of transmitters in vesicles plasma membrane.
o Packaging of neurotransmitters into vesicles or o The Rab3A cycle targets vesicles to their release
granules sites. Rab3A complexed to GTP binds to synaptic
o Vesicle Types: vesicles. During the targeting of synaptic vesicles to
a. Small, Clear, Spheroid - Acetylcholine, the active zone, Rab3A hydrolysis may serve to
GABA, Glycine, Glutamate make a reversible reaction irreversible, preventing
b. Small with dense core - Catecholamines, vesicles from leaving the active zone once they
serotonin arrive. During fusion and exocytosis, Rab3A-GDP
c. Large with dense core - peptides dissociates from the vesicle. There is then an
exchange of GTP for GDP. This is followed by the
 Release of transmitters into the synaptic cleft
association of Rab3A-GTP with a new synaptic
1. Development of Action Potential – depolarizes the
vesicle thus completing the cycle.
presynaptic membrane
2. Opening of voltage-gated calcium channels  Molecular Basis for fusion and exocytosis: The SNARE
3. Entry of calcium hypothesis
4. Binding of calcium with release sites o Vesicle and target membrane compartments have
5. Binding of vesicles with release sites (NB: each distinct receptors – the v-SNARES and t-SNARES
vesicle contains ~2000-10000 molecules) that mediate docking and fusion. Following fusion,
6. Exocytosis two cytoplasmic proteins, NSF (Neurexin/N-
7. Recycling of transmitter vesicles Ethylmaleimide-sensitive Factor) and SNAP
(Soluble NSF Attachment Protein), bind to the
SNARE complex and disassemble it

C. Synaptic Cleft: Processes

 Removal of transmitters via:
o Diffusion
o Enzymatic destruction
o Re-uptake

D. Post-synaptic Cell: Processes

 Receptor proteins in the postsynaptic terminal
Figure 7. Steps in the Release of Neurotransmitters. o Components
 Binding component
 Vesicular proteins  Ionophore component
o Synapsins  Ion channel
 Synapsin I - Fast event that closes within milliseconds
 Between synaptic vesicle and cytoskeletal - Either cation channels (usually Na+) or
elements anion channels (usually Cl-)
o Rab3A, Rab3C - Cation channels: lined up with negatively-
 Vesicle trafficking within the cell and vesicle charged residues to attract cations and
targeting within nerve terminal repel anions (opened by excitatory
neurotransmitters)
- Anion channels: small for hydrated
cations, but big enough to let anions pass
(opened by inhibitory neurotransmitters)

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 2nd messenger activators

- With repeated activation, the transmitter,
acting through PKA, will phosphorylate,
one or more transcriptional regulatory
proteins that activate gene expression.
Gene activation results in a protein that
produces more enduring closure of the
channel and changes in neuronal
excitability lasting days or weeks.
 Processes in the postsynaptic membrane
o Excitation
 Opening of Na+ channels
 Depressed conduction through K+ or Cl-
channels, or both
 Various changes in internal metabolism of
the postsynaptic neuron Figure 10. Temporal and Spatial Summation
o Inhibition
 Opening of Cl- channels If the membrane potential rises high enough, an action
 Increased conductance of K+ out of the potential can be generated through:
neuron 1. Spatial summation
 Activating receptor enzymes inhibiting 2. Temporal summation
cellular metabolic activity
 Two types of Receptors:
o Ionotropic Receptors: Directly gated
o Metabotropic Receptors: Indirectly gated

Figure 11. Direct Inhibition

IV. Overall Process

Figure 9. Two Types of Gating.  Action potential reaches the synaptic knob opening the
Ca2+ channels there
 Electrical events  Ca2+ causes the release of neurotransmitters across
the synaptic cleft.
Table 2. Distinguishing properties of EPSP and IPSP.
EPSP IPSP  Neurotransmitters bind to receptors in the postsynaptic
Excitatory Postsynaptic Inhibitory Postsynaptic Potential membrane causing certain ion channels to open.
Potential  EPSP
Increase excitability Decrease excitability o Na+ and K- channels open.
Depolarization Hyperpolarizing response o Na+ rushes in faster than K- rushes out causing the
Local response Ionic Basis: increase chloride or inside of the post synaptic membrane to become
potassium conductance more positive.
Graded Direct inhibition o This depolarization is the Excitatory postsynaptic
Non-propagated potential
o The EPSP reaches the threshold potential, an
 Resting Membrane potential action potential is initiated
o Valued at -65mV, which is less negative than the  IPSP
-95mV at the peripheral nerves and in muscle fibers o K+ and or Cl- channels open.
o Reason: the presence of ions allow electrical o Outward rush of K+ and/or inward rush of Cl-
gradient caused the postsynaptic membrane to become
o Consequence: allows variable excitation or less positive (more negative)
inhibition o This hyperpolarization is the inhibitory
 The Nernst Potential: potential (EMF) that exactly postsynaptic potential
opposes the movement of a specific ion o The postsynaptic membrane is now less likely to
o EMF = ±61 x log ([in]/[out]) (where EMF value is reach the threshold potential, initiation of an action
positive for anions and negative for cations) potential is thus inhibited
o For Na+: +65mV. but actual EMF is -65mV, hence the
V. Synaptic Delay
need for a Na-pump to expel Na+
o For K+: -86mV. more negative, so K+ tends to diffuse  0.5ms
out of the neurons  Interval before a response is obtained in the
o For Cl-: -70mV. small difference - very slight influx into postsynaptic neuron after an impulse reaches the
the neurons presynaptic terminals
 Time it takes for synaptic mediator to be released and
to act on the membrane of the postsynaptic cell
 Slowed conduction in polysynaptic pathways

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VIII. Importance of Synapses

VI. Synaptic Integration
1. Summation 1. Processing of information (learning)
2. Facilitation 2. Storage of information (memory)
3. Inhibition 3. Filtration of information
 Direct 4. Action of drugs (neuropharmacology)
 Indirect 5. Causes of mental health disorders
o Renshaw cell – inhibits motor neurons
adjacent to a motor neuron that is stimulated
IX. References
(lateral inhibition)
o Presynaptic Purbes, Neurosciences (3rd ed.). retrieved from
4. Factors affecting synaptic transmission: http://www.zoology.ubc.ca/.../synapses%20-
a) pH %20presynaptic.htm. date of retrieval: 4 August 2015
i. Alkalosis: increases excitability
ii. Acidosis: decreases excitability Guyton, A.C. and Hall, J.E. Textbook of Medical Physiology.
b.) Hypoxia: decreases excitability (11th ed.) USA: Elsevier Inc. 2006. Chapter 46
c.) Drugs
- Caffeine, theophylline, strychnine
- Increases excitability X. Quiz

Questions:

1.) True or False: There is no cytoplasmic continuity in the

electrical synapse

2.) True or False: Gray’s type II category of synaptic

membrane differentiations is symmetrical

3.) True or False: Gap Junctions are bridges of high-resistance

through which ions pass with difficulty.

4.) True or False: Connexons are components of the synaptic

cleft.
Figure 12. Presynaptic Inhibition and Facilitation.
5.) True or False: Chemical synapse is more abundant as
VII. Organization of Neural Pools
compared to electrical synapse

1. Convergence 6.) What is CMTX?

2. Divergence
3. Serial processing 7.) What is the agent of transmission in an electrical synapse?
4. Reverberation
5. Parallel – similar to circuits

Answers:

1.) False

2.) True

3.) False

4.) False

5.) True

6.) Charcot- Marie Tooth Disease

7.) Ion current

Figure 13. Organization of Neural Pools

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