Chapter 05: Synaptic Transmission
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Transcript Chapter 05: Synaptic Transmission
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
+
+
+
-
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