SYNAPTIC TRANSMISSION
Introduction
• SYNAPTIC TRANSMISSION
•
The process by which neurons transfer information at a synapse
•
Charles Sherrington (1897) : named ‘Synapse’
• Chemical synapse vs. Electrical synapse
•
Otto Loewi (1921) : Chemical synapses
•
Edwin Furshpan and David Potter (1959) : Electrical synapses
• John Eccles (1951) : Glass microelectrode
Types of Synapses
• Electrical Synapses
•
Direct transfer of ionic current from
one cell to the next
•
Gap junction
 The membranes of two cells are held
together by clusters of connexins
 Connexon
 A channel formed by six
connexins
 Two connexons combine to from a
gap junction channel
 Allows ions to pass from one cell
to the other
 1-2 nm wide : large enough for
all the major cellular ions and
many small organic molecules to
pass
Types of Synapses
• Electrical Synapses
•
Cells connected by gap junctions are said to be “electrically
coupled”
 Flow of ions from cytoplasm to cytoplasm bidirectionally
 Very fast, fail-safe transmission
 Almost simultaneous action potential generations
•
Common in mammalian CNS as well as in invertebrates
• Electrical synapses
•
Postsynaptic potential
(PSP)
 Caused by a small
amount of ionic
current that flow
into through the gap
junction channels
 Bidirectional
coupling
 PSP generated by a single electrical synapse is small (~1
mV)
 Several PSPs occuring simultaneously may excite a neuron
to trigger an action potential
• Electrical synapses
•
High temporal precision
•
Paired recording reveals
synchronous voltage responses
upon depolarizing or
hyperpolarizing current injections
•
Often found where normal
function requires that the
neighboring neurons be highly
synchronized
•
Oscillations, brain rhythm, state
dependent…
Types of Synapses
• Chemical Synapses
•
Synaptic cleft : 20-50 nm wide
(gap junctions : 3.5 nm)
•
Adhere to each other by the
help of a matrix of fibrous
extracellular proteins in the
synaptic cleft
•
Presynaptic element (= axon
terminal) contains
 Synaptic vesicles
 Secretory granules (~100nm)
(=dense-core vesicles)
•
Membrane differentiations
 Active zone
 Postsynaptic density
• Chemical Synapses vs Electrical synapses
Types of Synapses
• CNS Synapses
•
Axodendritic: Axon to dendrite
•
Axoaxonic: Axon to axon
•
Axosomatic: Axon to cell body
•
Dendrodendritic: Dendrite to
dendrite
Types of Synapses
• CNS Synapses
•
Gray’s Type I: Asymmetrical, excitatory
•
Gray’s Type II: Symmetrical, inhibitory
Types of Synapses
• The Neuromuscular Junction (NMJ)
•
Synapses between the axons of
motor neurons of the spinal cord
and skeletal muscle
•
Studies of NMJ established
principles of synaptic
transmission
•
Fast and reliable synaptic
transmission(AP of motor neuron
always generates AP in the
muscle cell it innervates) thanks
to the specialized structural
features
 The largest synapse in the body
 Precise alignment of synaptic
terminals with junctional folds
Principles of Chemical Synaptic
Transmission
• Basic Steps
•
Neurotransmitter synthesis
•
Load neurotransmitter into synaptic vesicles
•
Vesicles fuse to presynaptic terminal
•
Neurotransmitter spills into synaptic cleft
•
Binds to postsynaptic receptors
•
Biochemical/Electrical response elicited in postsynaptic cell
•
Removal of neurotransmitter from synaptic cleft
• Must happen RAPIDLY!
Principles of Chemical Synaptic
Transmission
• Neurotransmitters
•
Amino acids
•
Amines
•
Peptides
Principles of Chemical Synaptic
Transmission
• Neurotransmitters
•
Amino acids and amines are stored in
synaptic vesicles
•
Peptides are stored in and released
from secretory granules
 Often coexist in the same axon
terminals
•
Fast synaptic transmission and
slower synaptic transmission
Principles of Chemical Synaptic
Transmission
• Neurotransmitter Synthesis and Storage
•
Natural building blocks vs specialized neurotransmitters
Principles of Chemical Synaptic
Transmission
• Neurotransmitter Release
•
Voltage-gated calcium channels open - rapid increase from 0.0002 mM to
greater than 0.1 mM
•
Exocytosis can occur very rapidly (within 0.2 msec) because Ca2+ enters
directly into active zone
 ‘Docked’ vesicles are
rapidly fused with
plasma membrane
 Protein-protein
interactions regulate
the process (e.g.
SNAREs) of ‘docking’
as well as Ca2+induced membrane
fusion
 Vesicle membrane
recovered by
endocytosis
Principles of Chemical Synaptic
Transmission
• Neurotransmitter Release
•
Reserve pool and Readily releasable pool (RRP)
Fig. 1. Scattered distribution of RRP vesicles
S. O. Rizzoli et al., Science 303, 2037 -2039 (2004)
Published by AAAS
Principles of Chemical Synaptic
Transmission
• Neurotransmitter Release
•
Secretory granules
 Released from membranes that are away from the active
zones
 Requires high-frequency trains of action potentials to be
released
 Ca2+ needs to be build up throughout the axon terminal
 Leisurely process (50 msec)
Principles of Chemical Synaptic
Transmission
• Neurotransmitter receptors:
•
Ionotropic: Transmitter-gated ion channels
 Ligand-binding causes a slight
conformational change that
leads to the opening of channels
 Not as selective to ions as
voltage-gated channels
 Depending on the ions that can
pass through, channels are either
excitatory or inhibitory
 Reversal potential
Principles of Chemical Synaptic
Transmission
• Excitatory and Inhibitory Postsynaptic Potentials:
•EPSP:Transient
postsynaptic membrane
depolarization by
presynaptic release of
neurotransmitter
•Ach- and glutamate-gated
channels cause EPSPs
Principles of Chemical Synaptic
Transmission
• Excitatory and Inhibitory Postsynaptic Potentials:
•IPSP: Transient
hyperpolarization of
postsynaptic membrane
potential caused by
presynaptic release of
neurotransmitter
•Glycine- and GABA-gated
channels cause IPSPs
Principles of Chemical Synaptic
Transmission
•
Metabotropic: G-protein-coupled receptors
 Trigger slower, longer-lasting and more diverse postsynaptic
actions
 Same neurotransmitter could exert different actions depending on
what receptors it bind to
Effector proteins
•
Autoreceptors: present on the presynaptic terminal
 Typically, G-protein coupled receptors
 Commonly, inhibit the release or synthesis of neurotransmitter
 Negative feedback
Principles of Chemical Synaptic
Transmission
• Neurotransmitter Recovery and Degradation
•
Clearing of neurotransmitter is necessary for the next round of synaptic
transmission
 Simple Diffusion
 Reuptake aids the diffusion
 Neurotransmitter re-enters presynaptic axon terminal or enters glial cells
through transporter proteins
 The transporters are to be distinguished from the vesicular forms
 Enzymatic destruction
 In the synaptic cleft
 Acetylcholinesterase (AchE)
•
Desensitization:
 Channels close despite the continued presence of ligand
 Can last several seconds after the neurotransmitter is cleared
 Nerve gases (e.g. sarin) inhibit AchE - increased Ach - AchR desensitization muscle paralysis
Principles of Chemical Synaptic
Transmission
• Neuropharmacology
•
The study of effect of drugs on nervous system tissue
•
Receptor antagonists: Inhibitors of neurotransmitter receptors
 e.g. Curare binds tightly to Ach receptors of skeletal muscle
•
Receptor agonists: Mimic actions of naturally occurring
neurotransmitters
 E.g. Nicotine binds and activates the Ach receptors of skeletal muscle
(nicotinic Ach receptors)
•
Toxins and venoms
•
Defective neurotransmission: Root cause of neurological and
psychiatric disorders
Principles of Synaptic Integration
• Synaptic Integration
•
Process by which multiple synaptic potentials combine within one
postsynaptic neuron
•
Basic principle of neural computation
• The Integration of EPSPs
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Principles of Synaptic Integration
• The integration of EPSPs
•
Quantal Analysis of EPSPs
 Synaptic vesicles: Elementary units of synaptic transmission
 Contains the same number of transmitter molecules (several
thousands)
 Postsynaptic EPSPs at a given synapse is quantized = The
amplitude of EPSP is an integer multiple of the quantum
 Quantum: An indivisible unit determined by
 the number of transmitter molecules in a synaptic vesicle
 the number of postsynaptic receptors available at the
synapse
 Miniature postsynaptic potential (“mini”) is generated by
spontaneous, un-stimulated exocytosis of synaptic vesicles
 Quantal analysis: Used to determine number of vesicles that release
during neurotransmission
 Neuromuscular junction: About 200 synaptic vesicles, EPSP of
40mV or more
 CNS synapse: Single vesicle, EPSP of few tenths of a millivolt
Principles of Synaptic Integration
• EPSP Summation
•
Allows for neurons to perform sophisticated computations
•
Integration: EPSPs added together to produce significant
postsynaptic depolarization
•
Spatial summation : adding together of EPSPs generated
simultaneously at different synapses
•
Temporal
summation :
adding together
of EPSPs
generated at the
same synapse in
rapid succession
(within 1-15
msec of one
another)
Principles of Synaptic Integration
• The Contribution of Dendritic Properties to Synaptic Integration
•
Dendrite as a straight cable : EPSPs have to travel down to
spike-initiation zone to generate action potential
•
Membrane depolarization falls off exponentially with increasing
distance
 Vx = Vo/ex/ 
 Vo : depolarization at the
origin
  : Dendritic length constant
 Distance where the
depolarization is 37% of
origin (V= 0.37 Vo)
 In reality, dendrites have
branches, changing diameter..
Principles of Synaptic Integration
• The Contribution of Dendritic Properties to Synaptic Integration
•
Length constant ()
 An index of how far depolarization can spread down a dendrite or an axon
 Depends on two factors
 internal resistance (ri) : the resistance to current flowing longitudinally
down the dendrite
 membrane resistance (rm) : the resistance to current flowing across the
membrane
 While ri is relatively constant (largely determined by the diameter of
dendrite and electrical property of cytoplasm) in a mature neuron, rm
changes from moment to moment (depends on the number of opne
channels)
•
Excitable Dendrites
 Dendrites of neurons having voltage-gated sodium, calcium, and potassium
channels
 Can act as amplifiers (vs. passive) : EPSPs that are large enough to open
voltage-gated channels can reach the soma by the boost offered by added
currents through VGSCs
 Dendritic sodium channels: May carry electrical signals in opposite direction,
from soma outward along dendrites : back-propagating action potential might
inform the dendrites that an action potential has been generated
Principles of Synaptic Integration
• Inhibition
Action of synapses to take membrane potential away from action
potential threshold
•
IPSPs and Shunting Inhibition
 Excitatory vs. inhibitory synapses: Bind different
neurotransmitters, allow different ions to pass through
channels
 GABA or glycine :: Cl Ecl : -65 mV, at resting membrane potential no IPSP is visible
Principles of Synaptic Integration
• Shunting Inhibition
•
Inhibiting current flow from soma to axon hillock
• The Geometry of Excitatory and Inhibitory Synapses
•
Inhibitory synapses
 Gray’s type II morphology
 Clustered on soma and near
axon hillock
 Powerful position to influence
the activity of the
postsynaptic neuron
Principles of Synaptic Integration
• Modulation
•
Synaptic transmission that does not directly evoke EPSPs and
IPSPs but instead modifies the effectiveness of EPSPs generated by
other synapses with transmitter-gated ion channels
•
Mediated by G-protein-coupled neurotransmitter receptors
•
Example: Activating NE β receptor