Brain Science Fundamentals
Christopher Fiorillo
BiS 328, Fall 2011
042 350 4326, [email protected]
Part 7: Synaptic Transmission
Reading: Bear, Connors, and Paradiso
Chapter 5
Assistant: Sora Yun <[email protected]>
A Single Neuron with Synapses in Yellow
Synapses Are Physical Contacts between Neurons
that Enable Fast Transmission of Information
• Types of Synaptic Contacts
–
–
–
–
Axodendritic: Axon to dendrite
Axosomatic: Axon to cell body
Axoaxonic: Axon to axon
Dendrodendritic: Dendrite to dendrite
Two Types of Transmission
• Chemical Transmission
– 1921- Otto Loewi
• Electrical Transmission
– 1959- Furshpan and Potter
• There was a long-lasting debate about
whether transmission was chemical or
electrical. Both occur, but chemical
transmission is much more common.
Direction of Information Flow
• Information usually flows in one direction
– First neuron = Presynaptic neuron
– Target cell = Postsynaptic neuron
Postsynaptic neuron
Presynaptic neuron
Electrical Synapses Are Composed of Gap Junctions
• Gap junction are large channels
– Large enough (1-2 nm) to allow all ions plus other small molecules to
pass
– A Connexon spans the membrane - formed by six connexin proteins
• Cells are said to be “electrically coupled”
– Flow of ions from cytoplasm to cytoplasm
Electrical Synapses
• Very fast transmission
– Chemical transmission has a delay
• Postsynaptic potentials (PSPs) have the same
form as the presynaptic potential, but are smaller
• Most electrical synapses are bidirectional, but
some are unidirectional
A Chemical Synapse
• The synaptic cleft is a 20-50 nm gap between the
presynaptic terminal and the postsynpatic membrane
• Neurotransmitter is released into the cleft and activates
postsynaptic receptors
Electron Micrograph of a Chemical Synapse
• Synaptic Vesicles
– Made of phospholipid
membrane
– 50 nm in diameter
– Filled with molecules of
neurotransmitter
• Dense-core Vesicles
– Contains peptide
neurotransmitters
• Vesicles release
neurotransmitter when they
fuse with the presynaptic
membrane
Synapses Vary in Size and Strength
• Larger synapses allow
the presynaptic neuron
to have a larger and
more reliable effect on
the postsynaptic neuron
Two Synaptic Morphologies
• Symmetrical: usually inhibitory
• Asymmetrical: usually excitatory
• Neurotransmitter Synthesis and Storage
– Small neurotransmitters (amines, amino acids)
• Synthesized in vesicles within terminal
– Peptides
• Synthesized within soma and transported to terminal
• Basic Steps of Chemical Synaptic Transmission
– Action potential invades synaptic terminal
– Depolarization-activated Ca2+ channels open
– Ca2+ triggers vesicles to fuse into membrane of presynaptic terminal (exocytosis)
– Neurotransmitter spills into synaptic cleft
– Binds to postsynaptic receptors
– Biochemical/Electrical response elicited in postsynaptic cell
– Removal of neurotransmitter from synaptic cleft
– New vesicles formed by endocytosis
– Vesicles are filled with neurotransmitter and prepared for release
Removal of Neurotransmitter from the Synaptic Cleft
• Removal of neurotransmitter is important in order to
limit the duration of postsynaptic stimulation. This
enables high frequencies of information transmission
• Three Mechanisms
– Diffusion
– Reuptake: Transporters bind neurotransmitter and transport
it to inside of presynaptic terminal
• This is the most important mechanism for removing
neurotransmitters
• Cocaine and Prozac (fluoxetine) block reuptake of dopamine and
serotonin
– Enzymatic destruction in synaptic cleft
• Acetylcholineesterase rapidly eliminates acetylcholine by
hydrolysis to acetate and choline. This is the only major
neurotransmitter eliminated from the synaptic cleft by an enzyme.
The Neuromuscular Junction
• Studies of NMJ
established principles
of synaptic
transmission
• Synapses between
neurons are very
similar to NMJ
• Acetylcholine is the
neurotransmitter at
NMJ
Neurotransmitter Release is Quantal
• A action potential causes the release of a
discrete number of vesicles (or quanta)
– Neuromuscular junction: About 200 synaptic
vesicles, EPSP of 40mV or more
– CNS synapse: Single vesicle, EPSP of few tenths of
a millivolt
• Each vesicle contains about the same amount of
neurotransmitter
– Quantal content (the amount of transmitter per
vesicle) is not a physiologically important variable
• Spontaneous release of a single vesicle causes a
miniature postsynaptic potential (current)
– Often called a “mini”
Miniature Postsynaptic Currents Are
Caused by Release of a Single Vesicle
• “Minis” (mEPSCs and mIPSCs) are caused by spontaneous
release of a single vesicle in the absence of a presynaptic
action potential
• Minis can be calcium-dependent or independent
• Time course of mPSCs are identical to PSCs
• ~3 ms for EPSC
• ~30 ms for IPSC
• Amplitude of mPSC depends on postysynaptic receptors
• vesicles all contain the same amount of transmitter,
which can saturate postsynaptic receptors
• Frequency of mPSCs depends on presynaptic factors
• At most synapses, < 0.01 mPSC / second
• At some synapses, > 0.1 mPSC / second
Glutamate EPSC
Release Probability
• Not every action potential evokes vesicle
release
• Release probability (Pr) given action
potential
• Some synapses release multiple vesicles,
but most release just 0 or 1 vesicle
• Pr depends primarily on calcium
concentration in terminal’s cytosol, which
depends on:
– Presence or absence of an action potential
– Recent history of action potentials
– Activation of neurotransmitter receptors on
synaptic terminal
Pr varies from
one synapse to
another. A
typical value is
0.3.
Analogies between Presynaptic Terminals and Somatodendritic Compartment
Somatodendritic
Compartment
Synaptic
Terminal
Analog Variable Membrane Voltage Calcium
Concentration
Digital Output Action Potential Vesicle Release
Imaginary
Quantity
Instantaneous Firing
Rate (spike
probability)
Release Probability
Additional Analogies
Somatodendritic
Compartment
Synaptic
Terminal
Inputs
Synaptic inputs and
voltage-regulated
ion channels
The Action Potential
(plus the same inputs as
at the soma, but with few
synapses)
Excitatory
Processes
Deplarization (for
example, by
summation of EPSPs)
Facilitation (by
calcium)
Inhibitory
Processes
Hyperpolarization,
Depression (for
shunting of by K+ and
example, by depletion
C- channels, inactivation
of docked vesicles)
of Na+ channels
Paired-Pulse Depression and Facilitation
•
PPD and PPF are universal features of synapses.
•
Some synapses show PPD, some show PPF, and some show
both
– All synapses may have multiple mechanisms mediating both
depression and facilitation
•
PPD and PPF are caused primarily by a decrease or increase,
respectively, in vesicle release probability
•
Electrical stimuli (each lasting about 0.2 ms) are applied to a
brain slice maintained in vitro. This evokes postsynaptic
potentials (or currents, if measured in voltage clamp).
– Excitatory Postsynaptic Potential (Current): EPSP (EPSC)
– Inhibitory Postsynaptic Potential (Current): IPSP (IPSC)
•
Each stimulus evokes action potentials in many axons, and it
therefore causes vesicle release from many terminals
– A PSP (PSC) is caused by release of multiple vesicles (quanta)
• But if a low stimulation current is used, it is possible to stimulate only
a single axon, and that axon may have only one release site. In this
case, some stimuli may not release any vesicles.
•
The amplitude of a PSP (PSC) depends on the release
probability at stimulated synapses
Presynaptic [Ca2+] at
PF synapse
PPD and PPF at 3 synapses. 10
stimuli at 50 Hz (20 ms intervals)
Causes of Synaptic Depression and Facilitation
•
The most common cause of facilitation is an increased
calcium concentration
– This is due primarily to the fact that calcium is cleared slowly after
an action potential
•
The most common cause of depression is a loss of
“docked” (releasable) vesicles
– Most vesicles in the terminal are “undocked,” meaning that they
are not close to the membrane and bound to the vesicle-release
machinery
– There may be just one docked vesicle. Once it is released, it
takes time for another vesicle to be docked and ready to release.
– The rate of recovery from depression is increased by calcium. It
facilitates the docking of vesicles.
•
There are many ways in which release probability might be
modified
– Changes in membrane voltage
– Changes in the properties of ion channels, particularly calcium
channels, that are activated during the action potential
– Modification of proteins involved in vesicle release
•
There are probably multiple depressing and facilitating
processes happening simultaneously at each synapse.
Presynaptic [Ca2+]
at PF synapse
PPD and PPF at 3 synapses. 10
stimuli at 50 Hz (20 ms intervals)
Modulation of Release Probability by Presynaptic Neurotransmitter Receptors
Suppression of glutamate EPSCs by
adenosine receptors
Presynaptic [Ca2+] at PF synapse
is suppressed by cannabinoid
receptor activation
• Neurotransmitter receptors on presynaptic terminals act to
augment or suppress release probability
– These receptors therefore alter PPD or PPF
• Many receptors suppress vesicle release, including
“autoreceptors”
– Suppression often occurs through inhibition of Ca2+
channels and activation of K+ channels
How can we know whether a change in amplitude of a
synaptic potential is pre- or postsynaptic?
Suppression of glutamate EPSCs by adenosine
receptors
•
Two Easy Tests:
– Paired-pulse ratio (PPF or PPD)
• A change suggests a presynaptic effect
• No change suggests a postsynaptic effect
– Minis
• A change in frequency suggests a presynaptic effect
• A change in amplitude suggests a postsynaptic effect
•
These tests are not definitive; there are exceptions to these rules
Why are presynaptic terminals so complex?
• The release of neurotransmitters is very highly regulated.
• It is similar in this respect to the occurrence of action potentials.
• Presynaptic terminals may have the same basic function as the
somato-dendritic compartment of neurons.
– They may signal “prediction error”
– Thus a vesicle is released when the presynaptic terminal fails to
predict the occurrence of a action potential
– The complexity is caused by the integration of multiple sources of
information
• It may seem strange that the presynaptic terminal should function in a
manner that is so similar to the soma of the neuron. But, usually, the
soma and the presynaptic terminal are far apart. If the presynaptic
neuron should be regulated by the postsynaptic neuron and other
neurons that are close to the presynaptic terminal, then it is more
efficient to transmit information over a short distance to the
presynaptic terminal, rather than over a long distance to the soma or
dendrites of the presynaptic neuron.
Synaptic Integration
• Synaptic Integration: The process by which multiple synaptic
potentials sum together within one postsynaptic neuron
• This occurs in the dendrites and soma
• The “decision” point in most neurons is the axon hillock, where
the neuron “decides” whether to emit an action potential
Synaptic Inhibition
• Inhibition
– Takes membrane potential away from action potential
threshold
– Excitatory vs. inhibitory synapses: Bind different
neurotransmitters, allow different ions to pass through
channels
• Most synaptic inhibition is mediated by GABA-gated Cl- channels
• ECl- is -65 mV
• If membrane potential is less negative than -65mV, GABA mediates
hyperpolarizing IPSP.
• Two Mechanisms of Inhibition:
– Hyperpolarization
– Shunting Inhibition: Inhibiting current flow from dendrites
and soma to axon hillock
“Shunting Inhibition”
• Increasing membrane
conductance will decrease
membrane space constant
• Therefore, opening any channel
will cause an EPSP to decay
over a shorter distance
• This is called “shunting”
inhibition. It prevents
depolarizing current from
reaching the axon hillock and
eliciting an action potential.
• By opening Cl- channels,
GABA can cause a shunting
inhibition even if it causes a
depolarization towards ECl.
A Single Neuron with Synapses in Yellow
Synaptic Plasticity
• The strength of a synapse can change; it is “plastic”
– A neuron can therefore select its own synapses
• Synaptic plasticity is thought to be the main
mechanism of learning and memory
• Synaptic plasticity has probably been the most
popular topic in neuroscience for the last 30 - 50
years
• Synaptic plasticity plays a critical and necessary
role in many computational neuroscience models
and in all artificial neural networks
• We will cover synaptic plasticity from both
computational and mechanistic perspectives in
future lectures
Scores on the first Exam
Frequency
Mean: 70
Range: 22 - 90
15.00
100.00%
11.25
75.00%
7.50
50.00%
3.75
25.00%
0
0%
0~5
11~15
21~25
31~35
41~45
51~55
0
61~65
71~75
81~85
91~95