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Synaptic transmission
Purkinje cells in the cerebellum
Synaptic endings
cerebellar Purkinje cell
The human brain contains at least 100 billion neurons, each with the ability to influence many other
cells; highly efficient and sophisticated communication mechanisms are required
→ this is enabled by synapses, the functional contacts between neurons
Study of activated synapse
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Synaptic transmission
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Types of synapses
Chemical synapse
Electrical synapse
Synaptic
cleft
At chemical synapses, there is no
intercellular continuity, and thus no direct
flow of current between pre‐ and
postsynaptic neurons.
Synaptic current flows across the
postsynaptic membrane in response to the
secretion of neurotransmitters, which open
or close postsynaptic ion channels.
At electrical synapses, gap junctions
between
pre‐
and
postsynaptic
membranes permit current to flow
passively through intercellular channels.
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Electrical synapses
Gap
junctions
consist
of
hexameric complexes formed by
subunits called connexons
The membranes of the two communicating neurons come
extremely close at the synapse, and are actually linked together
by an intercellular specialization called gap junction.
Neuroscience, 4th Edition, Figure 5.1a
Gap junctions contain precisely aligned, paired channels forming
a pore of dimensions much larger than the voltage‐gated ion
channels → a variety of substances other than ions can diffuse
between the cytoplasms of the neurons.
Electrical synapses work by allowing ionic current to flow passively through the gap junction pores; the
driving force is the potential difference generated locally by the action potential (AP depolarizes the
presynaptic membrane, where the postsynaptic membrane is still at resting conditions)
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Electrical synapses
Communication using gap junctions offers several advantages:
∙ current can flow in either direction, depending on which
member of the couple pair is invaded by an action potential
→ bidirectional communication
∙ passive current flow across the junction is virtually
instantaneous → extraordinarily fast transmission (without
the typical delay of chemical synapses)
Electrical synapses allow
synchronization
of
electrical
activity
in
hippocampal neurons.
Neuron
1
and
2
connected through a
electrical
synapse.
Generation of an AP in
neuron 1 often result in a
synchronized firing of an
AP in neuron 2.
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Rapid transmission of signal at an electrical
synapse of a crayfish. An AP in the presynaptic
neuron causes postsynaptic neuron to be
depolarized within a fraction of a millisecond.
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Chemical synapses
Neuroscience, 4th Edition, Figure 5.1b
There is not intercellular continuity in chemical
synapses.
The space between pre‐ and postsynaptic neurons,
the synaptic cleft, is substantially greater at
chemical synapses than at electrical ones
The key feature is the presence of small,
membrane‐bounded organelles called synaptic
vesicles within the presynaptic terminal.
These vesicles are filled with one or more
neurotransmitters, the chemical signals secreted
from the presynaptic neuron.
These chemical agents acts as messengers
between the communicating neurons. The
secreted neurotransmitters open or close
postsynaptic ligand‐gated ion channels after
binding to specific receptor molecules, and thus
eliciting an action potential in the postsynaptic
membrane.
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Chemical synapses
‐ When an AP invades the terminal of the
presynaptic cell, voltage‐gated Ca2+ ion
channels are activated.
‐ The steep Ca2+ concentration gradient (10‐3
M external vs 10‐7 M internal) results into a
fast influx of Ca2+ ions.
‐ Transient elevation of the concentration of
Ca2+ ions in the presynaptic neuron causes
the vesicles to fuse with the presynaptic
membrane → the content of the vesicles is
released into the cleft (exocytosis).
‐ Neurotransmitters diffuse across the cleft
and bind to specific receptors on the
membrane of the postsynaptic neuron, which
causes ion channels of the postsynaptic
membrane to open (or close).
‐ This neurotransmitter‐induced current flow
alters the conductance and membrane
potential of the postsynaptic neuron,
increasing or decreasing the probability of
action potential firing.
Neuroscience, 4th Edition, Figure 5.3
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The discovery of neurotransmitter release
/ 1926, Otto Loewi
‐ Two frogs’ hearts isolated and perfused; the perfusate flowing through the stimulated heart is
collected and transferred to the second heart.
‐ Electrical stimulation of the vagus nerve slows the heartbeat of the stimulated heart
→ the second heart, even without stimulation, reduces its beating frequency
Neuroscience, 4th Edition, Figure 5.4
‐ The released substance was referred to as “vagus substance”; later on was shown to be
acetylcholine (ACh)
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Neurotransmitters
Criteria that define a neurotransmitter
1. The molecule must be present within the presynaptic
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
Neuroscience, 4th Edition, Figure 6.1
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Postsynaptic receptors families
Ligand‐gated ion channels (ionotropic): combine transmitter binding and channel functions into a
single molecular entity. They are typically made up of 4 to 5 protein subunits, each of which contribute
to the pore of the ion channel
Neuroscience, 4th Edition, Figure 5.23
G‐protein‐coupled receptors (metabotropic): ion movement results from one or more metabolic steps.
Do not have ion channels as part of their structure. Affect channels by the activation of G‐proteins,
which dissociate from the receptor and interact directly with the channel or bind to other effector
proteins, such as enzymes, that make intracellular messengers →open/close ion channels
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Quantal release of neurotransmitters
A study case: ACh release at neuromuscular junctions
“Quantal components of the end‐plate potential”, del Castillo J & Katz B, J Physiol (1954) 124, 560–573.
The experiment
∙ The axon of the motor neuron innervating the muscle fiber is stimulated with
an extracellular electrode
∙ An intracellular microelectrode is inserted into the postsynaptic muscle cell to
record its electrical responses
∙ An action potential in the presynaptic motor neuron
can elicit a transient depolarization of the postsynaptic
muscle fiber: this is called an end plate potential (EPP)
End plate of a
neuromuscular junction
∙ EPP are typically above the threshold, and can elicit a
postsynaptic action potential, which causes the muscle
fiber to contract.
Acetylcholine
∙ There exist a pronounced delay between the
stimulation of the presynaptic motor neuron and the
postsynaptic action potential, which is typical of all
chemical synapses.
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Quantal release of neurotransmitters
A study case: ACh release at neuromuscular junctions
“Quantal components of the end‐plate potential”, del Castillo J & Katz B, J Physiol (1954) 124, 560–573.
∙ In the absence of stimulation of the presynaptic neuron,
spontaneous changes in the muscle cell membrane are observed.
∙ These potential changes have the same shape than EPPs, but their
magnitude is much smaller, ~ 0.5mV (50 mV for EPPs)
∙ EPPs and these small events are sensitive to pharmacological
agents that block postsynaptic ACh receptors.
→ the spontaneous events are called miniature end plate
potential (MEPPs)
low [Ca2+] bath
∙ If the neuromuscular junction is bathed in a low [Ca2+] solution,
neurotransmitter secretion is strongly reduced → reduction of
the EPP magnitude below the threshold for AP.
∙ In this situation, very small EPP are recorded, with a magnitude
varying from trial to trial, and of similar shape of the
spontaneous MEPP.
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Jose A. Garrido | [email protected]
Quantal release of neurotransmitters
A study case: ACh release at neuromuscular junctions
“Quantal components of the end‐plate potential”, del Castillo J & Katz B, J Physiol (1954) 124, 560–573.
No EPP in
response to
stimulation
Quantized distribution of EPP amplitudes evoked in a low
Ca2+ solution
Prediction
of statistical
model
Peaks of EPP amplitudes tend to occur in integer
multiples (“quanta”) of the mean amplitude of MEPPS.
The number of such quanta contained in a given EPP
varied randomly with time.
“Quantal” fluctuations in the amplitude of EPPs indicate that
EPPs are made up of individual units, each equivalent to a
MEPP response occurs in units about the size of single MEPPs
distribution of spontaneous
MEPP amplitudes
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Quantal release of neurotransmitters
A Poisson distribution
The number of quanta that occurred for a given EPP as a result of nerve stimulation can be
described by a Poisson distribution (del Castillo & Katz, 1954)
P ( n,  ) 
n
n!
e   where n=0, 1, 2, 3, …
μ corresponds to the mean value or the expected
value of the number of occurrences obtained from
a large population of the same event
The Poisson distribution gives the probability for
the number of occurrences (n=0,1,2,…) of a given
event taking place within a certain time or space
‐ the events occur independently of each other
‐ the probability for each single event is small
It is assumed that each EPP is composed of the sum of a number n of units (“quanta”), with
mean amplitude and standard deviation identical to the mean amplitude and standard deviation
of the MEPP
m
mean amplitude of EPP
 number of units that on average enter on a single EPP as a
mean amplitude of MEPP result of nerve stimulation
if the number of units that enter in a EPP follows a Poisson distribution, the mean value m should
correspond to the mean value of the distribution → m=μ
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Quantal release of neurotransmitters
A Poisson distribution
In the case of a Poisson distribution, the mean value can be obtained by determining the
probability that the event does not occur
P (0,  )  e   
 number of absent responses 

number
of nerve
impulses


number of absent responses
number of nerve impulses
  ln
Thus, in the case of a Poisson distribution
 number of absent responses 
mean amplitude of EPP
 ln

mean amplitude of MEPP
number
of nerve
impulses


slope 1
mean amplitude of EPP
mean amplitude of MEPP
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Quantal release of neurotransmitters
Typically, it has been shown that ACh is highly concentrated in the synaptic vesicles of motor
neurons, about 100mM.
Considering that a small synaptic vesicle is about 50 nm in size, then approximately 6,000
molecules are contained in a single vesicle. Of them, only about 1500 ACh actually bind to
postsynaptic receptors (10‐20% efficiency)
Fine structure of vesicle fusion sites
in
presynaptic
terminals.
Proteinaceous structures arrange
vesicles in rows
Electron microscopy showing the
fusion of synaptic vesicles in
presynaptic terminals of frog motor
neurons
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Role of Ca2+
The voltage clamp detects current flowing
across the presynaptic membrane when the
membrane potential is depolarized.
Pharmacological agents that block currents
flowing through Na+ and K+ channels reveal a
remaining inward Ca2+ current, which triggers
transmitter secretion → EPP
Upon treatment with cadmium (a Ca2+
channel blocker) eliminates both the
presynaptic Ca2+ current and the postsynaptic
response .
Neuroscience, 4th Edition, Figure 5.10
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Molecular mechanism of transmitter secretion
Model of the molecular organization of a
synaptic vesicle.
The cytoplasmic surface of the vesicle
membrane is densely covered by
proteins, only 70% of which are shown
here
Biosensors and Bioelectronics (WS13/14)
Neuroscience, 4th Edition, Figure 5.14
Precisely how an increase in presynaptic Ca2+ concentration goes on to trigger vesicle fusion and
neurotransmitter release is not understood
Proteins in the presynaptic membrane and in
the vesicle membrane form macromolecular
complexes bringing both membranes into
close apposition.
Binding of Ca2+ to receptor proteins in the
vesicle (synaptotagmin) seems to induce
chemical changes (allowing the insertion of
this protein into a membrane & binding to
other proteins) that produce the final fusion of
these membranes .
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Postsynaptic membrane permeability changes
The binding of neurotransmitters (e.g. ACh) to postsynaptic
receptors opens ion channels in the postsynaptic membrane
Outside‐out patch clamp measurement
of single ACh receptor current
Individual ACh
receptors only
open briefly
The opening of a large number of channels is
synchronized by the brief duration of ACh secretion from
presynaptic terminals. End plate current (EPC):
macroscopic current resulting from the summed opening
of many ion channels
The EPC is normally inwards, it causes the postsynaptic
membrane potential to depolarize. This depolarization
change is the EPP, which might elicit an AP.
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Cell‐transistor electronic interface
Neuronal networks
neuron 1
neuron 2
Stimulator
Receptor
Extended neuronal network
Distributed stimulator/receptors
P. Fromherz
Field Effect Transistor array as a
versatile and functional platform for
cell recording and stimulation
Neurons on CMOS transistors
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