NESC 2570 Lecture Notes - Lecture 8: Inhibitory Postsynaptic Potential, Reversal Potential, Membrane Potential
27 Jun 2018
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Synapses:
Synapse: specialized zone of contact at which one neuron communicates with another
Points of contact between neurons that serve for communication - there are an incredible amount of
synapses in the brain
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Neurons in the human brain: 1011- 1012
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The average neuron receives 1000 synapses ( some neurons in the cerebellum: 10,000 synaptic contacts)
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Number of synapses in the human brain: 1015 - 1016
Electrical Synapses: Junctions between neurons permitting direct, passive flow of electrical current
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Not as common - they big channels between two connective neurons and they can transmit lots
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Direct link for ion transport and this will result in the communication of electrical synapse without the
transduction into chemical synapse
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Big channels between two connective neurons and can transmit all ions - direct link for ion transport
which will result in communication of electrical signal without transducing them into chemical signals
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Chemical Synapses: Junctions between neurons that communicate via the secretion of neurotransmitters
They are the most common synapses
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This is the manipulation of electrical signals into the chemical release
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Post synaptic neuron detects the neurotransmitter and turns it back into an electrical signal
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Electrical Synapses
Structure of electrical synapses
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Which molecules diffuse through electrical synapses?
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Properties of transmission at electrical synapses:
Directionality of transmission
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Velocity of transmission
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Sign and amplitude of transmitted and potential changes
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Regulation of transmission
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Occurrence and function of electrical synapses
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Nothing but gap junctions - gap junctions are connections between two neurons
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n extremely close contact (3 nm between membranes)
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Structure of Electrical Synapses
Electrical synapses are gap junctions- gap junctions are how cells can communicate, they are channels in
between them which are made up of two hemichannels
Plasma membranes closely apposed (3nm)
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Precisely aligned, paired channels (connexons) made up of connexins:
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Gap junction will have thousands of connexons which are subunits of hemichannels
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Most of the time, gap junction channels are closed so only a fraction of them are open at a time
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Pores of connexons are fairly wide (14-20 A in size) which allows the passage of all major ions
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Different connexin isoforms determine the transmission properties of the electrical synapse
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What diffuses through neuronal gap junctions?
All ions (ex. Potassium, sodium, calcium and chlorine)
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These channel pores are actually quite big so that allows for all the ion passages
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They are wide enough to allow secondary messengers to pass through as well
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Small molecular weight compounds
Ex. Second messengers such as cAMP and IP3
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Experiment: Path clamping a pair of electrically coupled neurons
Depolarizing current is injected so an action potential is triggered - what happens in the post synaptic neuron?
You will see a slight depolarization but no action potential - this is because only a fraction of sodium will
make it across the gap junction.
This occurs quickly
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If the reverse experiment is done, and a hyperpolarization current is injected, the post synaptic neuron will
also slightly hyperpolarize so the amplitude is smaller - you will get less of a potential change in the post
synaptic neuron
Sodium will flow from the other side (this will hyperpolarize the neuron)
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Velocity is really fast, you see this change almost immediately
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If depolarization is initiated slowly, this is different from a quickly initiated depolarization (why and how)
Two rooms that are connected by doors and there are equal number of people on each side. Room A
gets crowded and then people leave Room A because it gets crowded. But in Room B someone
calls "fire alarm" so everyone in room B rush to the door, however it was announced it was a false
alarm so people disperse again. People in Room A who didn't hear the fire alarm wouldn't know
much about it because only a few people would have gotten through the door because the original
occupation of Room A was large
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Properties of Transmission at Electrical Synapses
Connexons can be phosphorylated by kinases which can manipulate the opening and closing of gap junction
channels
Most of the time gap junction channels are closed which allows for ample regulation
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When phosphorylation causes more closing which means less conductance of an electrical synapse and
more of an amplitude as the current makes it from the pre synaptic neuron to the post synaptic neuron
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Bidirectional - occasionally, electrical synapses are rectifying due to the voltage dependence of gap junction
channel opening
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Velocity - transmission rapid synaptic latency is in the order of .1ms
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Sign and amplitude of transmitted changes
Same sign smaller amplitude - ex. A 10mV hyperpolarization may lead to a 1 mV hyperpolarization post
synaptically
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Slow potential changes are much better transmitted than fast changes (such as action potentials)
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Regulation of Electrical Transmission
Most gap junction channels closed, regulated to alter fraction of open channels:
Most of the time, gap junctions are closed which allows for ample regulation
Less of a conductance of an electrical synapse and more of a decay of the amplitude as the current
makes it from one neuron to the next
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Connexin phosphorylation
Extracellular signals activate protein kinases which phosphorylate connexins
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Example Horizontal Cells: D1 receptor --> adenylyl cyclase --> cAMP --> protein kinase A -->
phosphorylation of connexins --> Gap junction channels less open
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Depending on the connexin type, phosphorylation can have the opposite effect and tend to open gap
junction channels
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Intracellular calcium concentration
Gap junctions close in response to pathologically high calcium concentrations
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If you have a calcium overload in one cell that is about to die, you don't want this high
concentration to carry on to all the other connected neurons that are healthy
So this leads to closing of the gap junctions and shows why gap junctions are closed by
calcium concentration
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Electrical potential of membranes also regulate the opening of gap junctions
If a membrane is really depolarized, it can lead to the closing of gap junction channels
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If a membrane potential is consistently depolarizing a neuron, this means that the neuron may not
be doing too well so the ceasing of the continuation of the current will restrict the other cells from
failure
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Differences between the electrically connected cells
Large differences in membrane potential between electrically connected cells tend to close gap
junction channels. Dependent on connexin composition
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If membrane is depolarized, this causes the depolarization of gap junction channels
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Occurrence and Function of Electrical Synapses
Class/Family/ Species
Electrical Synapse Between
Function
Crayfish
Giant fiber --> Motor Neuron
Fast flight response - this is because
currents can move very quickly
Aplysia
Between motor neurons responsible for the
discharge of ink.It has a set full of ink, so
when a predator comes, it releases ink to
confuse it. The muscles that allow for this
ejection are connected to sensory neurons
via electrical synapses
Defense against predators
Teleost
Cochlear nerve terminals --> Mauthner
Neuron
Fast tail-flip response (escape)
Mammals
Retinal neurons (photoreceptors, bipolar
and ganglion cells; horizontal and amacrine
cells)
Improvement of sensitivity and spacial
discrimination; dynamic adjustment of
bipolar and ganglion cell centre-
surround receptive fields to
illumination (horizontal cells)
Mammals
GABAergic internerons in the neocortex,
hippocampus, thalamus, cerebellum and
spinal cord
Synchronization of activity;
generation of oscillatory activity
Mammals
Glutamatergic projection neurons in the
inferior olive (climbing fibers and possibly
hippocampus
Synchronization of activity
Electrical Synapses in Aplysia Califonica
Motorneurons in control ink discharge are connected via electrical synapses, allowing them to fire
synchronously, thus providing rapid and complete ink discharge
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Slugs are not very fast, so they prevent being eaten by releasing ink and it gets cloudy and the predator gets
confused and peaces out.
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The neurons that stimulate the release of this ink are connected to sensory neurons by electrical syanpses
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Electrical Synapses in Fish
Mauthner neuron (mauther neurons are connected to auditory sensory neurosn via synapses that are both
electrical and chemical so that action potentials can be transmitted very quickly so we have a fast escape
response) are large reiculospinal neurons in fish and amphibia that mediate escape responses. In teleosts,
Mauther neurons receive mixed electrical and chemical synaptic input from auditory afferents
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Electrical Synapses in the Retina
Retina is full of electrical synapses between the various receptor cells
Bipolar cells and ammacrine cells
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Interneurons and amacrine cells
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They allow for processing of visual information
Horizontal cells are for lateral inhibition of input - prevents other photoreceptors from activating
nearby and
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All of the horizontal cells are coupled to each other which allows them to inhibit all bipolar cells
and be activated at the same time
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Sometimes this is not desirable - think that you are getting up early in the morning but your friend
sleeping next to you doesn't have lecture until later, so you don't want to wake them. This makes it
difficult to navigate so you need every single photoreceptor and every single photon
Horizontal cells get uncoupled and close their electrical synapses and this works a phosphorylation
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Electrical synapses are closed by an electrical phosphorylation so lateral inhibition is a lot less so
photoreceptors can transmit their information to bipolar cells
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Electrical Synapses in the Neocortex
Excitatory vs inhibitory interneurons
GABA interneurons - are connected by synapses
Interneurons are supposed to be activated in a very similar manner
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If one gets depolarized, neighbouring interneurons of the same class will also get depolarized which
accounts for the rhythmic activity that can be detected in the cortex
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In the cortex we have excitatory projectatory neurons and inhibitory neurons (GABA)
Each class serves different functions
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All interneurons that do similar functions are connected by electrical synapses
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Interneurons are supposed to be activated in a very similar fashion, the idea is that sometimes you want to
have broad inhibition of all interneurons in each layer
These electrical synapses allows for this
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If one neuron gets depolarized, it will send its depolarization to all neighbouring neurons of the
same class
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This counts for oscillatory activity between neurons
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Chemical Synapses
Structure of chemical synapses
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Transmission at chemical synapses
How does an action potential invading a presynaptic bouton cause neurotransmitter release?
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How is neurotransmitter in the synapatic cleft detected and "translated" into changes in postsynaptic
membrane potential?
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Postsynaptic currents and potentials
What determines the time course of postsynaptic currents and potentials?
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What determines direction and amplitude of postsynaptic currents and potentials?
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Calculating the reverse potential of a channel
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What are excitatory postsynaptic currents and potentials?
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What are inhibitory post synaptic currents and potentials?
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Properties of chemical transmission
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Transduce an electrical synapse into a chemical synapse
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Structure of Chemical Synapses
Presynaptic Bouton: Specialization of the presynaptic neuron containing cellular component required for the
secretion of neurotransmitter
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Presynaptic Vesicle: Membrane vesicle of 35-50nm diameter; contains thousands of neurotransmitter
molecules
Vesicles dock to the plasma membrane and release neurotransmitter
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Active Zone: Proteinaceous structure at the presynaptic membrane required for efficient exocytosis of
neurotransmitter
A complex of proteins to allow vesicles to dock and eventually fuse with the plasma membrane so
neurotransmitter can be released
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Synaptic Cleft: extracellular space between presynaptic and postsynaptic membrane; width 20-40nm
Much larger than the electrically connected synapses
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The space is filled with extra cell proteins
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Postsynaptic Specialization: Proteinaceous structure at the postsynaptic membrane; contains neurotransmitter
receptors, proteins of intracellular signaling cascades (ex. Kinases) and scaffolding proteins, which link
receptors and signaling proteins to the cytoskeleton of the post synaptic neuron.
Need a lot of molecules to allow for the dynamic communication of neurotransmission release
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Commonly called the pre synaptic terminal
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Presynaptic specialization is presynaptic bouton
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Chemical Synapses are Not Created Equal
The structure of the post synaptic specialization is different in inhibitory and excitatory synapses
Asymmetrical (Gray's Type I) synapses (mostly excitatory)
Thicker
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Symmetrical (Gray's Type II) synapses (mostly inhibitory)
Allows us to be able to tell from an electromicrograph what kind of synapses you are looking at
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Vesicles containing peptide and monoamine neurotransmitters have a different ultrastructural appearance
Small synaptic vesicle with little electron density: amino acid neurotransmitters, acetylcholine, purine
neurotransmitters
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Small, electron-dense synaptic vesicles: monoamine neurotransmitters
Appear blackish on an electromicrograph
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Sometimes vesicles can get very large which commonly contain peptide neurotransmitters
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Sometimes vesicles can get very large and they contain peptide transmitters
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Different pre and postsynaptic structures can participate in synapse formation
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All contain vesicles, pre synaptic specializations and a post synaptic specialization but electromicrographs show
differences between synapses
Axospinous Synapses: synapses of axonal boutons onto spinous protrusions of dendrites: Excitatory
(glutamatergic) synapses
Spines receive synapses on axons that transverse the dendrite
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Axodendritic Synapses: synapses of axonal boutons onto dendritic shaft - inhibitory synapses
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Axosomatic synapses: synapses of axonal boutons onto neuronal soma that are frequently inhibitory
synapses
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Axo-axonic synapses: Synapses of axonal boutons onto axons or another axonal bouton - exclusively
inhibitory synapses
Can inhibit the release of neurotransmitter at that synapse
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Also synapses between dendrites, every now and then dendrites to dendrites will contact each other
and make inhibitory synapses
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Dendrodendritic synapses: synapses of dendritic segments containing synaptic vesicles onto another
dendrite - often reciprocal inhibitory synapses
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Neuromuscular Junction: of axonal boutons onto muscle fibre - excitatory (cholinrgic) synapse
Specialized synapses between neurons and muscle fires
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Transmission at Chemical Synapses: Sequence of Events
An action potential arrives at presynaptic bouton; voltage-gated sodium channels open
Depolarizes to threshold and leads to the opening of voltage gated calcium channels
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Voltage gated calcium channels open, and calcium flows into the cytosol
Calcium is a second messenger that binds to a sensor protein on the vesicles
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This protein allows for the fusion of the synaptic vesicle membrane with the plasma membrane
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Causes a fusion pore to form and allows for neurotransmitter to release into the synaptic cleft
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Neurotransmitter binds to specialized sensors on the post synaptic neuron
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The increased cytosolic calcium concentration causes a synaptic vesicle docked at the active zone to fuse with
the plasma membrane
Neurotransmitter is released into the synaptic cleft
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Neurotransmitter will bind to ionotropic receptors and metabotropic receptors
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Ionotropic Receptors
Are ligand gated ion channels where the ligand (neurotransmiter) binds to an extracellular site, leading to a
conformational change in the receptor's membrane spanning domain, which the opens an ion channel which
allows for the flow of ions from the extracellular site into the post synaptic neuron
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Ionotropic receptors are usually ion selective, allowing only passage of either
Chlorine or sodium and potassium or sodium, potassium and calcium
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Metabotropic Receptors
Are G-protein coupled receptors that are not ion channels themselves
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The ligand (neurotransmitter) binds to an extracellular site, leading to a conformational change in the receptor's
membrane spanning domain, which activates a G-protein bound to the receptor
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The activated g protein dissociates form the receptor and either and bind to the effector protein or an ion chanel
Binds directly to an ion channel and modulates its conductance or binds to the effector proteins (enzymes)
that modulate the concentrations of second messengers (such as cAMP, cGMP or IP3) which in turn
modulate ion channels
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Signal is transduced into opening and closing of ion channels
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G protein or second messenger modulated ion channels are usually ion selective
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Postsynaptic responses to activation of metabotropic receptors are usually slow and long lasting
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Both ionotropic receptors an metabotropic receptors modulate the flow of ions into the synaptic cleft
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Transmission at Chemical Synapses: Sequence of Events
An action potential arrives at presynaptic bouton and the voltage gated sodium channels open
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Voltage gated calcium channels open and calcium flows into the cytosol
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The increased cytosolic calcium concentration cases a synaptic vesicle docked at the active zone to fuse with
the plasma membrane.
Neurotransmitter is released into the synaptic cleft
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Neurotransmitter finds to
Iontropic receptors that leading directly to opening of ion channels
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Metabotropic receptors leading to opening or (sometimes closing) of ion channels via activation of G
proteins and modulation of second messenger cascades)
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The post synaptic current leads to a postsynaptic potential
Ie. A change in the potential of the postsynaptic membrane
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What processes turn chemical transmission off?
Voltage gated sodium channels inactivate - open only for a milisecond or so and then close again
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Voltage gated potassium channels open which repolarizes the presynaptic membrane
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Voltage gated calcium channels close after repolarization of the presynaptic membrane - calcium signals trigger
release
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Ion pumps re-establish ion gradients across the presynaptic membrane
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Neurotransmitter is removed from the synaptic cleft by transporters in neurons and surrounding glial cells
A lot of post synaptic receptors close even though there is binding of the ligand, this is called
desensitization
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Some ionotropic receptors desensitize and close in the continued presence of their ligand
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Post synaptic potentials spread throughout the dendrite and soma, and (if threshold to activate voltage gated
sodium channels is not reached) eventually dissipate
Once receptor/ion channels close on the post synaptic side, the membrane potential dissipates
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Time course of postsynaptic currents and potentials
Single ligand- gated ionotropic receptor: Neurotransmitter causes channel to open. Channel is open only for a
few ms, as the ligand unbinds and diffuses away
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Synapse - many neurotransmitter molecules exocytosed many ligand-gated channels (CNS Synapse: 102;
NMJ:106) open nearly simultaneously.
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Variability in timecourse of ligand unbinding causes some channels to close somewhat later than others
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The post synaptic current. i.e the sum of all channel currents, has a characteristic fat rise time (near
simultaneous ligand binding) and slower time to decay (variability in ligand unbinding)
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The postsynaptic potential has a similar, yet slightly slower timecourse
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Post synaptic current activates very quickly (less than a milisecond) and it decays much slower
Patch clamp electrophysiology - plasma membrane sticks to the pipette and you can record the current
that goes through ion channels within the membrane patch
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Adjust the voltage of the membrane patch or place neurotransmitters within the bath solution which
causes the opening of ligand gated ion channels
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Receptors are commonly quite quick at opening the channels
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Many can be activated at the same time, however they close one by one which causes a much slower
decay
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Potential change is even slower - when you have a fast input current due to a sodium influx, you will see a
change in the membrane voltage and then the depolarization dissipates much more slowly because the
acetylcholine receptors close one by one
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Direction and amplitude of postsynaptic currents: Qualitative description
Ions flow inside the cell when ionotropic receptors either flow inside or outside of the cell
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Flux of ions across membranes are determined by the electrochemical gradient; i.e. sum of membrane potential
and concentration gradient
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Also electrical - if the inside is more negative than the outside, it will drive positive ions into the cell because
opposite charges attract
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If membrane potential and concentration gradient oppose each other and are of same strength, the
electrochemical gradient is zero: reverse potential of the ion (and of all channels with selective permeability for
this ion)
Results in NO net flow of ions
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Forces due to the chemical gradient if it is equal in size as the electrical force acting on the ions but they
are working in the opposite direction, you will have no net flow of ions across the membrane. This is the
reversal potential
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Amplitude of Postsynaptic Currents and Potentials: Quantitative Description
The direction of a post synaptic current I is calculated using membrane potential (Vm) and the reverse potential
(Erev) of the ligand-gated ion channel:
Ohms Law: I=g (Vm- Erev)
G is the postsynaptic membrane conductance
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If Erev is more positive than Vmthe net current is inward (negative), if Erev is more negative than
Vm, the net current is outward (positive)
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The more different the membrane potential is than the reversal potential, the larger the current
When the membrane potential is such that the chemical gradient is equal and opposite of the
electrical gradient there is no net flow of ions across the membrane
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Current is zero
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However the more difference there are, the more ions will flow into and out of the cell - this is
Ohms law
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Current is dependent on how many ion channels you have and how well they conduct - the larger
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The amplitude of the post synaptic current depends on the number and conductance of open ligand-gated
ion channels and the magnitude of the difference between membrane potential and reversal potential
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Direction and amplitude of post synaptic potentials are also dependent on Vm, Erev and g: opening of
ligand-gated ion channels during synaptic transmission cases the post synaptic membrane potential to
change in the direction of the reversal potential of that ion channel
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Reversal Potential of an Ion Channel
The reversal potential of an ion channel is the membrane potential at which the net current through the channel
is zero
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If an ion channel is selective for a single ion, its reversal potential is the equilibrium potential for this ion (i.e.
the membrane potential at which there is no electrochemical driving force for this ion). The reversal potential
can be calculated according to the Nernst Equation
T is temperature (kelvin)
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Z charge of ion
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R is the gas constant
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F is the Faraday constant
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Numerator is the extracellular concentration of the ion
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Denominator is the intracellular concentration of the ion
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If an ion channel is permeable to two or more ions, its reversal potential somewhere in between the equilibrium
potentials for the individual ions can be calculated using the Goldman equation:
P = probability (some number between 0 and 1)
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Postsynaptic currents and potentail of synapses containing CL- channels
The reversal potential for a ligand gated chloride channel, assuming [Cl-]i= 15mM and [Cl-]o= 110mM (extra
cellular and intracellular chloride concentration in the mammalian CNS)
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At Vm< -50,mV the electrochemical driving force will cause chloride to flow out of the cell which
results in a negative current and a depolarizing potential and make the cell more positive
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At Vm = -50 mV no postsynaptic current and potential are absent
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At Vm> -50mV, electrochemical gradient forces chloride into the cell (positive current,
hyperpolarizing potential)
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Overall PSCs and PSPs change linearly with Vm
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Outward current means that positive currents are leaving the cell, or that negative currents are entering the cell
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Inward current means the opposite, that positive currents are entering the cells or that negative currents are
exiting the cell
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Excitatory Postsynaptic Currents and Potentials
Post synaptic currents and potentials are called excitatory postsynaptic currents and potentials (EPSCs and
EPSPs) if they increase the likelihood of a postsynaptic action potential occurring
Synapses at which neurotransmitter release leads to the generation of EPSPs are called excitatory
synapses
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If the reversal potential of the ligand gated ion channels carrying the postsynaptic current is more positive than
the action potential threshold, the postsynaptic potential facilitates action potential generation and is excitatory
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Examples for excitatory synapses:
Glutamatergic synapses in the CNS (contain sodium and potassium permeable glutamate receptors)
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Neuromuscular junctions (contain sodium and potassium permeable acetylcholine receptors)
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Inhibitory Postsynaptic Currents and Potentials
Postsynaptic currents and potentials are called inhibitory postsynaptic currents and potentials (IPSCs and IPSPs)
if they decrease the likelihood of a post synaptic action potential occurring
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Synapses at which neurotransmitter release leads to the generation of IPSPs are called inhibitory synapses
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If the reversal potential of the ligand-gated ion channels carrying the postsynaptic current is more negative than
the action potential threshold, the postsynaptic potential inhibits action potential generation
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If Erev<Vmthe IPSP inhibits action potential generation by hyperpolarizing the membrane potential
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If Erev>Vmthe IPSP is depolarizing but tends to keep the membrane potential at a value more negative than the
action potential threshold (Erev) making it harder for adjacent excitatory synapses to elicit an action potential.
Shunting inhibition
Depolarizes but never actually creates an action potential
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Ion channels open at the synapse and the membrane would depolarize but it can only do so until the
reversal potential of these channels, it cannot be more potential otherwise there will be no net flow of ions
across the membrane
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If you have an inhibitory synapse open that has a reversal potential above the membrane potential, it is
still inhibitory
Shunting inhibition
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Example for inhibitory synapses:
GABAergic synapses in the CNS (contain chloride permeable GABA receptors)
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Properties of Transmission at Chemical Synapses: Comparison with electrical synapses
Electrical Synapse
Chemical Synapse
Directionality of
transmission
Frequently bidirectional - can depolarize both
neuron A and neuron B
Unidirectional (transmission from pre to
postsynaptic neuron) - post synaptic
neuron cannot talk in the reverse
Synaptic delay
.1ms or less
.5-2ms
Direction of post
synaptic potential
change
Same as presynaptic potential change. Always
the same, if you have a depolarization in the
presynaptic neuron then you get a depolarization
in the post synaptic neuron
Either hyperpolarizing or depolarizing:
Depends on Vmand Erev of postsynaptic
ligand-gated ion channels
Amplitude of
postsynaptic
potential change
Fraction of presynaptic potential change; slow
potential changes transmitted better.
Depends on Vm, Erev of ion channel
involved, and on number and conductance
of opened channels
Transmission of
presynaptic
subthreshold activity
Yes
No; transmission requires presynaptic
action potential
Synaptic delay can be larger if it involves metabotropic receptors and modulation of second messenger
cascades
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Exception to this requirement: Photoreceptors and bipolar cells in the retina and hair cells in the inner ear
release neurotransmitter in response to graded receptor potentials
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Chemical synapses allow for much more alteration in post synaptic potential relative to pre synaptic
potential
Electrical synapses always have a 1 to 1 ratio from post synaptic to pre synaptic
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Stefan Krueger
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Monday mornings
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/
Electrical and Chemical Synapse
October)19,)2015
1:47)PM
Synapses:
Synapse: specialized zone of contact at which one neuron communicates with another
Points of contact between neurons that serve for communication - there are an incredible amount of
synapses in the brain
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Neurons in the human brain: 1011- 1012
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The average neuron receives 1000 synapses ( some neurons in the cerebellum: 10,000 synaptic contacts)
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Number of synapses in the human brain: 1015 - 1016
Electrical Synapses: Junctions between neurons permitting direct, passive flow of electrical current
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Not as common - they big channels between two connective neurons and they can transmit lots
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Direct link for ion transport and this will result in the communication of electrical synapse without the
transduction into chemical synapse
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Big channels between two connective neurons and can transmit all ions - direct link for ion transport
which will result in communication of electrical signal without transducing them into chemical signals
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Chemical Synapses: Junctions between neurons that communicate via the secretion of neurotransmitters
They are the most common synapses
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This is the manipulation of electrical signals into the chemical release
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Post synaptic neuron detects the neurotransmitter and turns it back into an electrical signal
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Electrical Synapses
Structure of electrical synapses
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Which molecules diffuse through electrical synapses?
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Properties of transmission at electrical synapses:
Directionality of transmission
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Velocity of transmission
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Sign and amplitude of transmitted and potential changes
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Regulation of transmission
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Occurrence and function of electrical synapses
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Nothing but gap junctions - gap junctions are connections between two neurons
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n extremely close contact (3 nm between membranes)
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Structure of Electrical Synapses
Electrical synapses are gap junctions- gap junctions are how cells can communicate, they are channels in
between them which are made up of two hemichannels
Plasma membranes closely apposed (3nm)
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Precisely aligned, paired channels (connexons) made up of connexins:
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Gap junction will have thousands of connexons which are subunits of hemichannels
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Most of the time, gap junction channels are closed so only a fraction of them are open at a time
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Pores of connexons are fairly wide (14-20 A in size) which allows the passage of all major ions
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Different connexin isoforms determine the transmission properties of the electrical synapse
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What diffuses through neuronal gap junctions?
All ions (ex. Potassium, sodium, calcium and chlorine)
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These channel pores are actually quite big so that allows for all the ion passages
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They are wide enough to allow secondary messengers to pass through as well
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Small molecular weight compounds
Ex. Second messengers such as cAMP and IP3
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Experiment: Path clamping a pair of electrically coupled neurons
Depolarizing current is injected so an action potential is triggered - what happens in the post synaptic neuron?
You will see a slight depolarization but no action potential - this is because only a fraction of sodium will
make it across the gap junction.
This occurs quickly
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If the reverse experiment is done, and a hyperpolarization current is injected, the post synaptic neuron will
also slightly hyperpolarize so the amplitude is smaller - you will get less of a potential change in the post
synaptic neuron
Sodium will flow from the other side (this will hyperpolarize the neuron)
○
Velocity is really fast, you see this change almost immediately
○
○
If depolarization is initiated slowly, this is different from a quickly initiated depolarization (why and how)
Two rooms that are connected by doors and there are equal number of people on each side. Room A
gets crowded and then people leave Room A because it gets crowded. But in Room B someone
calls "fire alarm" so everyone in room B rush to the door, however it was announced it was a false
alarm so people disperse again. People in Room A who didn't hear the fire alarm wouldn't know
much about it because only a few people would have gotten through the door because the original
occupation of Room A was large
○
○
○
Properties of Transmission at Electrical Synapses
Connexons can be phosphorylated by kinases which can manipulate the opening and closing of gap junction
channels
Most of the time gap junction channels are closed which allows for ample regulation
○
When phosphorylation causes more closing which means less conductance of an electrical synapse and
more of an amplitude as the current makes it from the pre synaptic neuron to the post synaptic neuron
○
Bidirectional - occasionally, electrical synapses are rectifying due to the voltage dependence of gap junction
channel opening
○
Velocity - transmission rapid synaptic latency is in the order of .1ms
○
Sign and amplitude of transmitted changes
Same sign smaller amplitude - ex. A 10mV hyperpolarization may lead to a 1 mV hyperpolarization post
synaptically
○
Slow potential changes are much better transmitted than fast changes (such as action potentials)
○
○
Regulation of Electrical Transmission
Most gap junction channels closed, regulated to alter fraction of open channels:
Most of the time, gap junctions are closed which allows for ample regulation
Less of a conductance of an electrical synapse and more of a decay of the amplitude as the current
makes it from one neuron to the next
○
○
Connexin phosphorylation
Extracellular signals activate protein kinases which phosphorylate connexins
○
Example Horizontal Cells: D1 receptor --> adenylyl cyclase --> cAMP --> protein kinase A -->
phosphorylation of connexins --> Gap junction channels less open
○
Depending on the connexin type, phosphorylation can have the opposite effect and tend to open gap
junction channels
○
○
Intracellular calcium concentration
Gap junctions close in response to pathologically high calcium concentrations
○
If you have a calcium overload in one cell that is about to die, you don't want this high
concentration to carry on to all the other connected neurons that are healthy
So this leads to closing of the gap junctions and shows why gap junctions are closed by
calcium concentration
○
○
○
Electrical potential of membranes also regulate the opening of gap junctions
If a membrane is really depolarized, it can lead to the closing of gap junction channels
○
If a membrane potential is consistently depolarizing a neuron, this means that the neuron may not
be doing too well so the ceasing of the continuation of the current will restrict the other cells from
failure
○
○
Differences between the electrically connected cells
Large differences in membrane potential between electrically connected cells tend to close gap
junction channels. Dependent on connexin composition
○
If membrane is depolarized, this causes the depolarization of gap junction channels
○
○
○
Occurrence and Function of Electrical Synapses
Class/Family/ Species
Electrical Synapse Between
Function
Crayfish
Giant fiber --> Motor Neuron
Fast flight response - this is because
currents can move very quickly
Aplysia
Between motor neurons responsible for the
discharge of ink.It has a set full of ink, so
when a predator comes, it releases ink to
confuse it. The muscles that allow for this
ejection are connected to sensory neurons
via electrical synapses
Defense against predators
Teleost
Cochlear nerve terminals --> Mauthner
Neuron
Fast tail-flip response (escape)
Mammals
Retinal neurons (photoreceptors, bipolar
and ganglion cells; horizontal and amacrine
cells)
Improvement of sensitivity and spacial
discrimination; dynamic adjustment of
bipolar and ganglion cell centre-
surround receptive fields to
illumination (horizontal cells)
Mammals
GABAergic internerons in the neocortex,
hippocampus, thalamus, cerebellum and
spinal cord
Synchronization of activity;
generation of oscillatory activity
Mammals
Glutamatergic projection neurons in the
inferior olive (climbing fibers and possibly
hippocampus
Synchronization of activity
Electrical Synapses in Aplysia Califonica
Motorneurons in control ink discharge are connected via electrical synapses, allowing them to fire
synchronously, thus providing rapid and complete ink discharge
○
Slugs are not very fast, so they prevent being eaten by releasing ink and it gets cloudy and the predator gets
confused and peaces out.
○
The neurons that stimulate the release of this ink are connected to sensory neurons by electrical syanpses
○
Electrical Synapses in Fish
Mauthner neuron (mauther neurons are connected to auditory sensory neurosn via synapses that are both
electrical and chemical so that action potentials can be transmitted very quickly so we have a fast escape
response) are large reiculospinal neurons in fish and amphibia that mediate escape responses. In teleosts,
Mauther neurons receive mixed electrical and chemical synaptic input from auditory afferents
○
Electrical Synapses in the Retina
Retina is full of electrical synapses between the various receptor cells
Bipolar cells and ammacrine cells
○
Interneurons and amacrine cells
○
They allow for processing of visual information
Horizontal cells are for lateral inhibition of input - prevents other photoreceptors from activating
nearby and
○
All of the horizontal cells are coupled to each other which allows them to inhibit all bipolar cells
and be activated at the same time
○
○
Sometimes this is not desirable - think that you are getting up early in the morning but your friend
sleeping next to you doesn't have lecture until later, so you don't want to wake them. This makes it
difficult to navigate so you need every single photoreceptor and every single photon
Horizontal cells get uncoupled and close their electrical synapses and this works a phosphorylation
○
Electrical synapses are closed by an electrical phosphorylation so lateral inhibition is a lot less so
photoreceptors can transmit their information to bipolar cells
○
○
○
Electrical Synapses in the Neocortex
Excitatory vs inhibitory interneurons
GABA interneurons - are connected by synapses
Interneurons are supposed to be activated in a very similar manner
○
If one gets depolarized, neighbouring interneurons of the same class will also get depolarized which
accounts for the rhythmic activity that can be detected in the cortex
○
○
○
In the cortex we have excitatory projectatory neurons and inhibitory neurons (GABA)
Each class serves different functions
○
All interneurons that do similar functions are connected by electrical synapses
○
Interneurons are supposed to be activated in a very similar fashion, the idea is that sometimes you want to
have broad inhibition of all interneurons in each layer
These electrical synapses allows for this
○
If one neuron gets depolarized, it will send its depolarization to all neighbouring neurons of the
same class
○
This counts for oscillatory activity between neurons
○
○
○
Chemical Synapses
Structure of chemical synapses
○
Transmission at chemical synapses
How does an action potential invading a presynaptic bouton cause neurotransmitter release?
○
How is neurotransmitter in the synapatic cleft detected and "translated" into changes in postsynaptic
membrane potential?
○
○
Postsynaptic currents and potentials
What determines the time course of postsynaptic currents and potentials?
○
What determines direction and amplitude of postsynaptic currents and potentials?
○
Calculating the reverse potential of a channel
○
What are excitatory postsynaptic currents and potentials?
○
What are inhibitory post synaptic currents and potentials?
○
○
Properties of chemical transmission
○
Transduce an electrical synapse into a chemical synapse
○
Structure of Chemical Synapses
Presynaptic Bouton: Specialization of the presynaptic neuron containing cellular component required for the
secretion of neurotransmitter
○
Presynaptic Vesicle: Membrane vesicle of 35-50nm diameter; contains thousands of neurotransmitter
molecules
Vesicles dock to the plasma membrane and release neurotransmitter
○
○
Active Zone: Proteinaceous structure at the presynaptic membrane required for efficient exocytosis of
neurotransmitter
A complex of proteins to allow vesicles to dock and eventually fuse with the plasma membrane so
neurotransmitter can be released
○
○
Synaptic Cleft: extracellular space between presynaptic and postsynaptic membrane; width 20-40nm
Much larger than the electrically connected synapses
○
The space is filled with extra cell proteins
○
○
Postsynaptic Specialization: Proteinaceous structure at the postsynaptic membrane; contains neurotransmitter
receptors, proteins of intracellular signaling cascades (ex. Kinases) and scaffolding proteins, which link
receptors and signaling proteins to the cytoskeleton of the post synaptic neuron.
Need a lot of molecules to allow for the dynamic communication of neurotransmission release
○
Commonly called the pre synaptic terminal
○
○
Presynaptic specialization is presynaptic bouton
○
Chemical Synapses are Not Created Equal
The structure of the post synaptic specialization is different in inhibitory and excitatory synapses
Asymmetrical (Gray's Type I) synapses (mostly excitatory)
Thicker
○
○
Symmetrical (Gray's Type II) synapses (mostly inhibitory)
Allows us to be able to tell from an electromicrograph what kind of synapses you are looking at
○
○
○
Vesicles containing peptide and monoamine neurotransmitters have a different ultrastructural appearance
Small synaptic vesicle with little electron density: amino acid neurotransmitters, acetylcholine, purine
neurotransmitters
○
Small, electron-dense synaptic vesicles: monoamine neurotransmitters
Appear blackish on an electromicrograph
○
Sometimes vesicles can get very large which commonly contain peptide neurotransmitters
○
○
Sometimes vesicles can get very large and they contain peptide transmitters
○
○
Different pre and postsynaptic structures can participate in synapse formation
○
All contain vesicles, pre synaptic specializations and a post synaptic specialization but electromicrographs show
differences between synapses
Axospinous Synapses: synapses of axonal boutons onto spinous protrusions of dendrites: Excitatory
(glutamatergic) synapses
Spines receive synapses on axons that transverse the dendrite
○
○
Axodendritic Synapses: synapses of axonal boutons onto dendritic shaft - inhibitory synapses
○
Axosomatic synapses: synapses of axonal boutons onto neuronal soma that are frequently inhibitory
synapses
○
Axo-axonic synapses: Synapses of axonal boutons onto axons or another axonal bouton - exclusively
inhibitory synapses
Can inhibit the release of neurotransmitter at that synapse
○
Also synapses between dendrites, every now and then dendrites to dendrites will contact each other
and make inhibitory synapses
○
○
Dendrodendritic synapses: synapses of dendritic segments containing synaptic vesicles onto another
dendrite - often reciprocal inhibitory synapses
○
Neuromuscular Junction: of axonal boutons onto muscle fibre - excitatory (cholinrgic) synapse
Specialized synapses between neurons and muscle fires
○
○
○
Transmission at Chemical Synapses: Sequence of Events
An action potential arrives at presynaptic bouton; voltage-gated sodium channels open
Depolarizes to threshold and leads to the opening of voltage gated calcium channels
○
○
Voltage gated calcium channels open, and calcium flows into the cytosol
Calcium is a second messenger that binds to a sensor protein on the vesicles
○
This protein allows for the fusion of the synaptic vesicle membrane with the plasma membrane
○
Causes a fusion pore to form and allows for neurotransmitter to release into the synaptic cleft
○
Neurotransmitter binds to specialized sensors on the post synaptic neuron
○
○
The increased cytosolic calcium concentration causes a synaptic vesicle docked at the active zone to fuse with
the plasma membrane
Neurotransmitter is released into the synaptic cleft
○
Neurotransmitter will bind to ionotropic receptors and metabotropic receptors
○
○
Ionotropic Receptors
Are ligand gated ion channels where the ligand (neurotransmiter) binds to an extracellular site, leading to a
conformational change in the receptor's membrane spanning domain, which the opens an ion channel which
allows for the flow of ions from the extracellular site into the post synaptic neuron
○
Ionotropic receptors are usually ion selective, allowing only passage of either
Chlorine or sodium and potassium or sodium, potassium and calcium
○
○
Metabotropic Receptors
Are G-protein coupled receptors that are not ion channels themselves
○
The ligand (neurotransmitter) binds to an extracellular site, leading to a conformational change in the receptor's
membrane spanning domain, which activates a G-protein bound to the receptor
○
The activated g protein dissociates form the receptor and either and bind to the effector protein or an ion chanel
Binds directly to an ion channel and modulates its conductance or binds to the effector proteins (enzymes)
that modulate the concentrations of second messengers (such as cAMP, cGMP or IP3) which in turn
modulate ion channels
○
Signal is transduced into opening and closing of ion channels
○
○
G protein or second messenger modulated ion channels are usually ion selective
○
Postsynaptic responses to activation of metabotropic receptors are usually slow and long lasting
○
Both ionotropic receptors an metabotropic receptors modulate the flow of ions into the synaptic cleft
○
Transmission at Chemical Synapses: Sequence of Events
An action potential arrives at presynaptic bouton and the voltage gated sodium channels open
○
Voltage gated calcium channels open and calcium flows into the cytosol
○
The increased cytosolic calcium concentration cases a synaptic vesicle docked at the active zone to fuse with
the plasma membrane.
Neurotransmitter is released into the synaptic cleft
○
○
Neurotransmitter finds to
Iontropic receptors that leading directly to opening of ion channels
○
Metabotropic receptors leading to opening or (sometimes closing) of ion channels via activation of G
proteins and modulation of second messenger cascades)
○
○
The post synaptic current leads to a postsynaptic potential
Ie. A change in the potential of the postsynaptic membrane
○
○
What processes turn chemical transmission off?
Voltage gated sodium channels inactivate - open only for a milisecond or so and then close again
○
Voltage gated potassium channels open which repolarizes the presynaptic membrane
○
Voltage gated calcium channels close after repolarization of the presynaptic membrane - calcium signals trigger
release
○
Ion pumps re-establish ion gradients across the presynaptic membrane
○
Neurotransmitter is removed from the synaptic cleft by transporters in neurons and surrounding glial cells
A lot of post synaptic receptors close even though there is binding of the ligand, this is called
desensitization
○
○
Some ionotropic receptors desensitize and close in the continued presence of their ligand
○
Post synaptic potentials spread throughout the dendrite and soma, and (if threshold to activate voltage gated
sodium channels is not reached) eventually dissipate
Once receptor/ion channels close on the post synaptic side, the membrane potential dissipates
○
○
Time course of postsynaptic currents and potentials
Single ligand- gated ionotropic receptor: Neurotransmitter causes channel to open. Channel is open only for a
few ms, as the ligand unbinds and diffuses away
○
Synapse - many neurotransmitter molecules exocytosed many ligand-gated channels (CNS Synapse: 102;
NMJ:106) open nearly simultaneously.
○
Variability in timecourse of ligand unbinding causes some channels to close somewhat later than others
○
The post synaptic current. i.e the sum of all channel currents, has a characteristic fat rise time (near
simultaneous ligand binding) and slower time to decay (variability in ligand unbinding)
○
The postsynaptic potential has a similar, yet slightly slower timecourse
○
Post synaptic current activates very quickly (less than a milisecond) and it decays much slower
Patch clamp electrophysiology - plasma membrane sticks to the pipette and you can record the current
that goes through ion channels within the membrane patch
○
Adjust the voltage of the membrane patch or place neurotransmitters within the bath solution which
causes the opening of ligand gated ion channels
○
Receptors are commonly quite quick at opening the channels
○
Many can be activated at the same time, however they close one by one which causes a much slower
decay
○
Potential change is even slower - when you have a fast input current due to a sodium influx, you will see a
change in the membrane voltage and then the depolarization dissipates much more slowly because the
acetylcholine receptors close one by one
○
○
Direction and amplitude of postsynaptic currents: Qualitative description
Ions flow inside the cell when ionotropic receptors either flow inside or outside of the cell
○
Flux of ions across membranes are determined by the electrochemical gradient; i.e. sum of membrane potential
and concentration gradient
○
Also electrical - if the inside is more negative than the outside, it will drive positive ions into the cell because
opposite charges attract
○
If membrane potential and concentration gradient oppose each other and are of same strength, the
electrochemical gradient is zero: reverse potential of the ion (and of all channels with selective permeability for
this ion)
Results in NO net flow of ions
○
Forces due to the chemical gradient if it is equal in size as the electrical force acting on the ions but they
are working in the opposite direction, you will have no net flow of ions across the membrane. This is the
reversal potential
○
○
Amplitude of Postsynaptic Currents and Potentials: Quantitative Description
The direction of a post synaptic current I is calculated using membrane potential (Vm) and the reverse potential
(Erev) of the ligand-gated ion channel:
Ohms Law: I=g (Vm- Erev)
G is the postsynaptic membrane conductance
○
If Erev is more positive than Vmthe net current is inward (negative), if Erev is more negative than
Vm, the net current is outward (positive)
○
○
The more different the membrane potential is than the reversal potential, the larger the current
When the membrane potential is such that the chemical gradient is equal and opposite of the
electrical gradient there is no net flow of ions across the membrane
○
Current is zero
○
However the more difference there are, the more ions will flow into and out of the cell - this is
Ohms law
○
Current is dependent on how many ion channels you have and how well they conduct - the larger
○
○
The amplitude of the post synaptic current depends on the number and conductance of open ligand-gated
ion channels and the magnitude of the difference between membrane potential and reversal potential
○
Direction and amplitude of post synaptic potentials are also dependent on Vm, Erev and g: opening of
ligand-gated ion channels during synaptic transmission cases the post synaptic membrane potential to
change in the direction of the reversal potential of that ion channel
○
○
Reversal Potential of an Ion Channel
The reversal potential of an ion channel is the membrane potential at which the net current through the channel
is zero
○
If an ion channel is selective for a single ion, its reversal potential is the equilibrium potential for this ion (i.e.
the membrane potential at which there is no electrochemical driving force for this ion). The reversal potential
can be calculated according to the Nernst Equation
T is temperature (kelvin)
○
Z charge of ion
○
R is the gas constant
○
F is the Faraday constant
○
Numerator is the extracellular concentration of the ion
○
Denominator is the intracellular concentration of the ion
○
○
If an ion channel is permeable to two or more ions, its reversal potential somewhere in between the equilibrium
potentials for the individual ions can be calculated using the Goldman equation:
P = probability (some number between 0 and 1)
○
○
Postsynaptic currents and potentail of synapses containing CL- channels
The reversal potential for a ligand gated chloride channel, assuming [Cl-]i= 15mM and [Cl-]o= 110mM (extra
cellular and intracellular chloride concentration in the mammalian CNS)
○
At Vm< -50,mV the electrochemical driving force will cause chloride to flow out of the cell which
results in a negative current and a depolarizing potential and make the cell more positive
○
At Vm = -50 mV no postsynaptic current and potential are absent
○
At Vm> -50mV, electrochemical gradient forces chloride into the cell (positive current,
hyperpolarizing potential)
○
Overall PSCs and PSPs change linearly with Vm
○
○
Outward current means that positive currents are leaving the cell, or that negative currents are entering the cell
○
Inward current means the opposite, that positive currents are entering the cells or that negative currents are
exiting the cell
○
Excitatory Postsynaptic Currents and Potentials
Post synaptic currents and potentials are called excitatory postsynaptic currents and potentials (EPSCs and
EPSPs) if they increase the likelihood of a postsynaptic action potential occurring
Synapses at which neurotransmitter release leads to the generation of EPSPs are called excitatory
synapses
○
○
If the reversal potential of the ligand gated ion channels carrying the postsynaptic current is more positive than
the action potential threshold, the postsynaptic potential facilitates action potential generation and is excitatory
○
Examples for excitatory synapses:
Glutamatergic synapses in the CNS (contain sodium and potassium permeable glutamate receptors)
○
Neuromuscular junctions (contain sodium and potassium permeable acetylcholine receptors)
○
○
Inhibitory Postsynaptic Currents and Potentials
Postsynaptic currents and potentials are called inhibitory postsynaptic currents and potentials (IPSCs and IPSPs)
if they decrease the likelihood of a post synaptic action potential occurring
○
Synapses at which neurotransmitter release leads to the generation of IPSPs are called inhibitory synapses
○
If the reversal potential of the ligand-gated ion channels carrying the postsynaptic current is more negative than
the action potential threshold, the postsynaptic potential inhibits action potential generation
○
If Erev<Vmthe IPSP inhibits action potential generation by hyperpolarizing the membrane potential
○
If Erev>Vmthe IPSP is depolarizing but tends to keep the membrane potential at a value more negative than the
action potential threshold (Erev) making it harder for adjacent excitatory synapses to elicit an action potential.
Shunting inhibition
Depolarizes but never actually creates an action potential
○
○
Ion channels open at the synapse and the membrane would depolarize but it can only do so until the
reversal potential of these channels, it cannot be more potential otherwise there will be no net flow of ions
across the membrane
○
If you have an inhibitory synapse open that has a reversal potential above the membrane potential, it is
still inhibitory
Shunting inhibition
○
○
○
Example for inhibitory synapses:
GABAergic synapses in the CNS (contain chloride permeable GABA receptors)
○
○
Properties of Transmission at Chemical Synapses: Comparison with electrical synapses
Electrical Synapse
Chemical Synapse
Directionality of
transmission
Frequently bidirectional - can depolarize both
neuron A and neuron B
Unidirectional (transmission from pre to
postsynaptic neuron) - post synaptic
neuron cannot talk in the reverse
Synaptic delay
.1ms or less
.5-2ms
Direction of post
synaptic potential
change
Same as presynaptic potential change. Always
the same, if you have a depolarization in the
presynaptic neuron then you get a depolarization
in the post synaptic neuron
Either hyperpolarizing or depolarizing:
Depends on Vmand Erev of postsynaptic
ligand-gated ion channels
Amplitude of
postsynaptic
potential change
Fraction of presynaptic potential change; slow
potential changes transmitted better.
Depends on Vm, Erev of ion channel
involved, and on number and conductance
of opened channels
Transmission of
presynaptic
subthreshold activity
Yes
No; transmission requires presynaptic
action potential
Synaptic delay can be larger if it involves metabotropic receptors and modulation of second messenger
cascades
○
Exception to this requirement: Photoreceptors and bipolar cells in the retina and hair cells in the inner ear
release neurotransmitter in response to graded receptor potentials
○
Chemical synapses allow for much more alteration in post synaptic potential relative to pre synaptic
potential
Electrical synapses always have a 1 to 1 ratio from post synaptic to pre synaptic
○
○
Stefan Krueger
○
Monday mornings
○
/
Electrical and Chemical Synapse
October)19,)2015
1:47)PM
Synapses:
Synapse: specialized zone of contact at which one neuron communicates with another
Points of contact between neurons that serve for communication - there are an incredible amount of
synapses in the brain
○
○
Neurons in the human brain: 1011- 1012
○
The average neuron receives 1000 synapses ( some neurons in the cerebellum: 10,000 synaptic contacts)
○
Number of synapses in the human brain: 1015 - 1016
Electrical Synapses: Junctions between neurons permitting direct, passive flow of electrical current
○
Not as common - they big channels between two connective neurons and they can transmit lots
○
Direct link for ion transport and this will result in the communication of electrical synapse without the
transduction into chemical synapse
○
Big channels between two connective neurons and can transmit all ions - direct link for ion transport
which will result in communication of electrical signal without transducing them into chemical signals
○
○
Chemical Synapses: Junctions between neurons that communicate via the secretion of neurotransmitters
They are the most common synapses
○
This is the manipulation of electrical signals into the chemical release
○
Post synaptic neuron detects the neurotransmitter and turns it back into an electrical signal
○
○
Electrical Synapses
Structure of electrical synapses
○
Which molecules diffuse through electrical synapses?
○
Properties of transmission at electrical synapses:
Directionality of transmission
○
Velocity of transmission
○
Sign and amplitude of transmitted and potential changes
○
○
Regulation of transmission
○
Occurrence and function of electrical synapses
○
Nothing but gap junctions - gap junctions are connections between two neurons
○
n extremely close contact (3 nm between membranes)
○
Structure of Electrical Synapses
Electrical synapses are gap junctions- gap junctions are how cells can communicate, they are channels in
between them which are made up of two hemichannels
Plasma membranes closely apposed (3nm)
○
Precisely aligned, paired channels (connexons) made up of connexins:
○
Gap junction will have thousands of connexons which are subunits of hemichannels
○
Most of the time, gap junction channels are closed so only a fraction of them are open at a time
○
○
Pores of connexons are fairly wide (14-20 A in size) which allows the passage of all major ions
○
Different connexin isoforms determine the transmission properties of the electrical synapse
○
What diffuses through neuronal gap junctions?
All ions (ex. Potassium, sodium, calcium and chlorine)
○
These channel pores are actually quite big so that allows for all the ion passages
○
They are wide enough to allow secondary messengers to pass through as well
○
Small molecular weight compounds
Ex. Second messengers such as cAMP and IP3
○
○
Experiment: Path clamping a pair of electrically coupled neurons
Depolarizing current is injected so an action potential is triggered - what happens in the post synaptic neuron?
You will see a slight depolarization but no action potential - this is because only a fraction of sodium will
make it across the gap junction.
This occurs quickly
○
○
If the reverse experiment is done, and a hyperpolarization current is injected, the post synaptic neuron will
also slightly hyperpolarize so the amplitude is smaller - you will get less of a potential change in the post
synaptic neuron
Sodium will flow from the other side (this will hyperpolarize the neuron)
○
Velocity is really fast, you see this change almost immediately
○
○
If depolarization is initiated slowly, this is different from a quickly initiated depolarization (why and how)
Two rooms that are connected by doors and there are equal number of people on each side. Room A
gets crowded and then people leave Room A because it gets crowded. But in Room B someone
calls "fire alarm" so everyone in room B rush to the door, however it was announced it was a false
alarm so people disperse again. People in Room A who didn't hear the fire alarm wouldn't know
much about it because only a few people would have gotten through the door because the original
occupation of Room A was large
○
○
○
Properties of Transmission at Electrical Synapses
Connexons can be phosphorylated by kinases which can manipulate the opening and closing of gap junction
channels
Most of the time gap junction channels are closed which allows for ample regulation
○
When phosphorylation causes more closing which means less conductance of an electrical synapse and
more of an amplitude as the current makes it from the pre synaptic neuron to the post synaptic neuron
○
Bidirectional - occasionally, electrical synapses are rectifying due to the voltage dependence of gap junction
channel opening
○
Velocity - transmission rapid synaptic latency is in the order of .1ms
○
Sign and amplitude of transmitted changes
Same sign smaller amplitude - ex. A 10mV hyperpolarization may lead to a 1 mV hyperpolarization post
synaptically
○
Slow potential changes are much better transmitted than fast changes (such as action potentials)
○
○
Regulation of Electrical Transmission
Most gap junction channels closed, regulated to alter fraction of open channels:
Most of the time, gap junctions are closed which allows for ample regulation
Less of a conductance of an electrical synapse and more of a decay of the amplitude as the current
makes it from one neuron to the next
○
○
Connexin phosphorylation
Extracellular signals activate protein kinases which phosphorylate connexins
○
Example Horizontal Cells: D1 receptor --> adenylyl cyclase --> cAMP --> protein kinase A -->
phosphorylation of connexins --> Gap junction channels less open
○
Depending on the connexin type, phosphorylation can have the opposite effect and tend to open gap
junction channels
○
○
Intracellular calcium concentration
Gap junctions close in response to pathologically high calcium concentrations
○
If you have a calcium overload in one cell that is about to die, you don't want this high
concentration to carry on to all the other connected neurons that are healthy
So this leads to closing of the gap junctions and shows why gap junctions are closed by
calcium concentration
○
○
○
Electrical potential of membranes also regulate the opening of gap junctions
If a membrane is really depolarized, it can lead to the closing of gap junction channels
○
If a membrane potential is consistently depolarizing a neuron, this means that the neuron may not
be doing too well so the ceasing of the continuation of the current will restrict the other cells from
failure
○
○
Differences between the electrically connected cells
Large differences in membrane potential between electrically connected cells tend to close gap
junction channels. Dependent on connexin composition
○
If membrane is depolarized, this causes the depolarization of gap junction channels
○
○
○
Occurrence and Function of Electrical Synapses
Class/Family/ Species
Electrical Synapse Between
Function
Crayfish
Giant fiber --> Motor Neuron
Fast flight response - this is because
currents can move very quickly
Aplysia
Between motor neurons responsible for the
discharge of ink.It has a set full of ink, so
when a predator comes, it releases ink to
confuse it. The muscles that allow for this
ejection are connected to sensory neurons
via electrical synapses
Defense against predators
Teleost
Cochlear nerve terminals --> Mauthner
Neuron
Fast tail-flip response (escape)
Mammals
Retinal neurons (photoreceptors, bipolar
and ganglion cells; horizontal and amacrine
cells)
Improvement of sensitivity and spacial
discrimination; dynamic adjustment of
bipolar and ganglion cell centre-
surround receptive fields to
illumination (horizontal cells)
Mammals
GABAergic internerons in the neocortex,
hippocampus, thalamus, cerebellum and
spinal cord
Synchronization of activity;
generation of oscillatory activity
Mammals
Glutamatergic projection neurons in the
inferior olive (climbing fibers and possibly
hippocampus
Synchronization of activity
Electrical Synapses in Aplysia Califonica
Motorneurons in control ink discharge are connected via electrical synapses, allowing them to fire
synchronously, thus providing rapid and complete ink discharge
○
Slugs are not very fast, so they prevent being eaten by releasing ink and it gets cloudy and the predator gets
confused and peaces out.
○
The neurons that stimulate the release of this ink are connected to sensory neurons by electrical syanpses
○
Electrical Synapses in Fish
Mauthner neuron (mauther neurons are connected to auditory sensory neurosn via synapses that are both
electrical and chemical so that action potentials can be transmitted very quickly so we have a fast escape
response) are large reiculospinal neurons in fish and amphibia that mediate escape responses. In teleosts,
Mauther neurons receive mixed electrical and chemical synaptic input from auditory afferents
○
Electrical Synapses in the Retina
Retina is full of electrical synapses between the various receptor cells
Bipolar cells and ammacrine cells
○
Interneurons and amacrine cells
○
They allow for processing of visual information
Horizontal cells are for lateral inhibition of input - prevents other photoreceptors from activating
nearby and
○
All of the horizontal cells are coupled to each other which allows them to inhibit all bipolar cells
and be activated at the same time
○
○
Sometimes this is not desirable - think that you are getting up early in the morning but your friend
sleeping next to you doesn't have lecture until later, so you don't want to wake them. This makes it
difficult to navigate so you need every single photoreceptor and every single photon
Horizontal cells get uncoupled and close their electrical synapses and this works a phosphorylation
○
Electrical synapses are closed by an electrical phosphorylation so lateral inhibition is a lot less so
photoreceptors can transmit their information to bipolar cells
○
○
○
Electrical Synapses in the Neocortex
Excitatory vs inhibitory interneurons
GABA interneurons - are connected by synapses
Interneurons are supposed to be activated in a very similar manner
○
If one gets depolarized, neighbouring interneurons of the same class will also get depolarized which
accounts for the rhythmic activity that can be detected in the cortex
○
○
○
In the cortex we have excitatory projectatory neurons and inhibitory neurons (GABA)
Each class serves different functions
○
All interneurons that do similar functions are connected by electrical synapses
○
Interneurons are supposed to be activated in a very similar fashion, the idea is that sometimes you want to
have broad inhibition of all interneurons in each layer
These electrical synapses allows for this
○
If one neuron gets depolarized, it will send its depolarization to all neighbouring neurons of the
same class
○
This counts for oscillatory activity between neurons
○
○
○
Chemical Synapses
Structure of chemical synapses
○
Transmission at chemical synapses
How does an action potential invading a presynaptic bouton cause neurotransmitter release?
○
How is neurotransmitter in the synapatic cleft detected and "translated" into changes in postsynaptic
membrane potential?
○
○
Postsynaptic currents and potentials
What determines the time course of postsynaptic currents and potentials?
○
What determines direction and amplitude of postsynaptic currents and potentials?
○
Calculating the reverse potential of a channel
○
What are excitatory postsynaptic currents and potentials?
○
What are inhibitory post synaptic currents and potentials?
○
○
Properties of chemical transmission
○
Transduce an electrical synapse into a chemical synapse
○
Structure of Chemical Synapses
Presynaptic Bouton: Specialization of the presynaptic neuron containing cellular component required for the
secretion of neurotransmitter
○
Presynaptic Vesicle: Membrane vesicle of 35-50nm diameter; contains thousands of neurotransmitter
molecules
Vesicles dock to the plasma membrane and release neurotransmitter
○
○
Active Zone: Proteinaceous structure at the presynaptic membrane required for efficient exocytosis of
neurotransmitter
A complex of proteins to allow vesicles to dock and eventually fuse with the plasma membrane so
neurotransmitter can be released
○
○
Synaptic Cleft: extracellular space between presynaptic and postsynaptic membrane; width 20-40nm
Much larger than the electrically connected synapses
○
The space is filled with extra cell proteins
○
○
Postsynaptic Specialization: Proteinaceous structure at the postsynaptic membrane; contains neurotransmitter
receptors, proteins of intracellular signaling cascades (ex. Kinases) and scaffolding proteins, which link
receptors and signaling proteins to the cytoskeleton of the post synaptic neuron.
Need a lot of molecules to allow for the dynamic communication of neurotransmission release
○
Commonly called the pre synaptic terminal
○
○
Presynaptic specialization is presynaptic bouton
○
Chemical Synapses are Not Created Equal
The structure of the post synaptic specialization is different in inhibitory and excitatory synapses
Asymmetrical (Gray's Type I) synapses (mostly excitatory)
Thicker
○
○
Symmetrical (Gray's Type II) synapses (mostly inhibitory)
Allows us to be able to tell from an electromicrograph what kind of synapses you are looking at
○
○
○
Vesicles containing peptide and monoamine neurotransmitters have a different ultrastructural appearance
Small synaptic vesicle with little electron density: amino acid neurotransmitters, acetylcholine, purine
neurotransmitters
○
Small, electron-dense synaptic vesicles: monoamine neurotransmitters
Appear blackish on an electromicrograph
○
Sometimes vesicles can get very large which commonly contain peptide neurotransmitters
○
○
Sometimes vesicles can get very large and they contain peptide transmitters
○
○
Different pre and postsynaptic structures can participate in synapse formation
○
All contain vesicles, pre synaptic specializations and a post synaptic specialization but electromicrographs show
differences between synapses
Axospinous Synapses: synapses of axonal boutons onto spinous protrusions of dendrites: Excitatory
(glutamatergic) synapses
Spines receive synapses on axons that transverse the dendrite
○
○
Axodendritic Synapses: synapses of axonal boutons onto dendritic shaft - inhibitory synapses
○
Axosomatic synapses: synapses of axonal boutons onto neuronal soma that are frequently inhibitory
synapses
○
Axo-axonic synapses: Synapses of axonal boutons onto axons or another axonal bouton - exclusively
inhibitory synapses
Can inhibit the release of neurotransmitter at that synapse
○
Also synapses between dendrites, every now and then dendrites to dendrites will contact each other
and make inhibitory synapses
○
○
Dendrodendritic synapses: synapses of dendritic segments containing synaptic vesicles onto another
dendrite - often reciprocal inhibitory synapses
○
Neuromuscular Junction: of axonal boutons onto muscle fibre - excitatory (cholinrgic) synapse
Specialized synapses between neurons and muscle fires
○
○
○
Transmission at Chemical Synapses: Sequence of Events
An action potential arrives at presynaptic bouton; voltage-gated sodium channels open
Depolarizes to threshold and leads to the opening of voltage gated calcium channels
○
○
Voltage gated calcium channels open, and calcium flows into the cytosol
Calcium is a second messenger that binds to a sensor protein on the vesicles
○
This protein allows for the fusion of the synaptic vesicle membrane with the plasma membrane
○
Causes a fusion pore to form and allows for neurotransmitter to release into the synaptic cleft
○
Neurotransmitter binds to specialized sensors on the post synaptic neuron
○
○
The increased cytosolic calcium concentration causes a synaptic vesicle docked at the active zone to fuse with
the plasma membrane
Neurotransmitter is released into the synaptic cleft
○
Neurotransmitter will bind to ionotropic receptors and metabotropic receptors
○
○
Ionotropic Receptors
Are ligand gated ion channels where the ligand (neurotransmiter) binds to an extracellular site, leading to a
conformational change in the receptor's membrane spanning domain, which the opens an ion channel which
allows for the flow of ions from the extracellular site into the post synaptic neuron
○
Ionotropic receptors are usually ion selective, allowing only passage of either
Chlorine or sodium and potassium or sodium, potassium and calcium
○
○
Metabotropic Receptors
Are G-protein coupled receptors that are not ion channels themselves
○
The ligand (neurotransmitter) binds to an extracellular site, leading to a conformational change in the receptor's
membrane spanning domain, which activates a G-protein bound to the receptor
○
The activated g protein dissociates form the receptor and either and bind to the effector protein or an ion chanel
Binds directly to an ion channel and modulates its conductance or binds to the effector proteins (enzymes)
that modulate the concentrations of second messengers (such as cAMP, cGMP or IP3) which in turn
modulate ion channels
○
Signal is transduced into opening and closing of ion channels
○
○
G protein or second messenger modulated ion channels are usually ion selective
○
Postsynaptic responses to activation of metabotropic receptors are usually slow and long lasting
○
Both ionotropic receptors an metabotropic receptors modulate the flow of ions into the synaptic cleft
○
Transmission at Chemical Synapses: Sequence of Events
An action potential arrives at presynaptic bouton and the voltage gated sodium channels open
○
Voltage gated calcium channels open and calcium flows into the cytosol
○
The increased cytosolic calcium concentration cases a synaptic vesicle docked at the active zone to fuse with
the plasma membrane.
Neurotransmitter is released into the synaptic cleft
○
○
Neurotransmitter finds to
Iontropic receptors that leading directly to opening of ion channels
○
Metabotropic receptors leading to opening or (sometimes closing) of ion channels via activation of G
proteins and modulation of second messenger cascades)
○
○
The post synaptic current leads to a postsynaptic potential
Ie. A change in the potential of the postsynaptic membrane
○
○
What processes turn chemical transmission off?
Voltage gated sodium channels inactivate - open only for a milisecond or so and then close again
○
Voltage gated potassium channels open which repolarizes the presynaptic membrane
○
Voltage gated calcium channels close after repolarization of the presynaptic membrane - calcium signals trigger
release
○
Ion pumps re-establish ion gradients across the presynaptic membrane
○
Neurotransmitter is removed from the synaptic cleft by transporters in neurons and surrounding glial cells
A lot of post synaptic receptors close even though there is binding of the ligand, this is called
desensitization
○
○
Some ionotropic receptors desensitize and close in the continued presence of their ligand
○
Post synaptic potentials spread throughout the dendrite and soma, and (if threshold to activate voltage gated
sodium channels is not reached) eventually dissipate
Once receptor/ion channels close on the post synaptic side, the membrane potential dissipates
○
○
Time course of postsynaptic currents and potentials
Single ligand- gated ionotropic receptor: Neurotransmitter causes channel to open. Channel is open only for a
few ms, as the ligand unbinds and diffuses away
○
Synapse - many neurotransmitter molecules exocytosed many ligand-gated channels (CNS Synapse: 102;
NMJ:106) open nearly simultaneously.
○
Variability in timecourse of ligand unbinding causes some channels to close somewhat later than others
○
The post synaptic current. i.e the sum of all channel currents, has a characteristic fat rise time (near
simultaneous ligand binding) and slower time to decay (variability in ligand unbinding)
○
The postsynaptic potential has a similar, yet slightly slower timecourse
○
Post synaptic current activates very quickly (less than a milisecond) and it decays much slower
Patch clamp electrophysiology - plasma membrane sticks to the pipette and you can record the current
that goes through ion channels within the membrane patch
○
Adjust the voltage of the membrane patch or place neurotransmitters within the bath solution which
causes the opening of ligand gated ion channels
○
Receptors are commonly quite quick at opening the channels
○
Many can be activated at the same time, however they close one by one which causes a much slower
decay
○
Potential change is even slower - when you have a fast input current due to a sodium influx, you will see a
change in the membrane voltage and then the depolarization dissipates much more slowly because the
acetylcholine receptors close one by one
○
○
Direction and amplitude of postsynaptic currents: Qualitative description
Ions flow inside the cell when ionotropic receptors either flow inside or outside of the cell
○
Flux of ions across membranes are determined by the electrochemical gradient; i.e. sum of membrane potential
and concentration gradient
○
Also electrical - if the inside is more negative than the outside, it will drive positive ions into the cell because
opposite charges attract
○
If membrane potential and concentration gradient oppose each other and are of same strength, the
electrochemical gradient is zero: reverse potential of the ion (and of all channels with selective permeability for
this ion)
Results in NO net flow of ions
○
Forces due to the chemical gradient if it is equal in size as the electrical force acting on the ions but they
are working in the opposite direction, you will have no net flow of ions across the membrane. This is the
reversal potential
○
○
Amplitude of Postsynaptic Currents and Potentials: Quantitative Description
The direction of a post synaptic current I is calculated using membrane potential (Vm) and the reverse potential
(Erev) of the ligand-gated ion channel:
Ohms Law: I=g (Vm- Erev)
G is the postsynaptic membrane conductance
○
If Erev is more positive than Vmthe net current is inward (negative), if Erev is more negative than
Vm, the net current is outward (positive)
○
○
The more different the membrane potential is than the reversal potential, the larger the current
When the membrane potential is such that the chemical gradient is equal and opposite of the
electrical gradient there is no net flow of ions across the membrane
○
Current is zero
○
However the more difference there are, the more ions will flow into and out of the cell - this is
Ohms law
○
Current is dependent on how many ion channels you have and how well they conduct - the larger
○
○
The amplitude of the post synaptic current depends on the number and conductance of open ligand-gated
ion channels and the magnitude of the difference between membrane potential and reversal potential
○
Direction and amplitude of post synaptic potentials are also dependent on Vm, Erev and g: opening of
ligand-gated ion channels during synaptic transmission cases the post synaptic membrane potential to
change in the direction of the reversal potential of that ion channel
○
○
Reversal Potential of an Ion Channel
The reversal potential of an ion channel is the membrane potential at which the net current through the channel
is zero
○
If an ion channel is selective for a single ion, its reversal potential is the equilibrium potential for this ion (i.e.
the membrane potential at which there is no electrochemical driving force for this ion). The reversal potential
can be calculated according to the Nernst Equation
T is temperature (kelvin)
○
Z charge of ion
○
R is the gas constant
○
F is the Faraday constant
○
Numerator is the extracellular concentration of the ion
○
Denominator is the intracellular concentration of the ion
○
○
If an ion channel is permeable to two or more ions, its reversal potential somewhere in between the equilibrium
potentials for the individual ions can be calculated using the Goldman equation:
P = probability (some number between 0 and 1)
○
○
Postsynaptic currents and potentail of synapses containing CL- channels
The reversal potential for a ligand gated chloride channel, assuming [Cl-]i= 15mM and [Cl-]o= 110mM (extra
cellular and intracellular chloride concentration in the mammalian CNS)
○
At Vm< -50,mV the electrochemical driving force will cause chloride to flow out of the cell which
results in a negative current and a depolarizing potential and make the cell more positive
○
At Vm = -50 mV no postsynaptic current and potential are absent
○
At Vm> -50mV, electrochemical gradient forces chloride into the cell (positive current,
hyperpolarizing potential)
○
Overall PSCs and PSPs change linearly with Vm
○
○
Outward current means that positive currents are leaving the cell, or that negative currents are entering the cell
○
Inward current means the opposite, that positive currents are entering the cells or that negative currents are
exiting the cell
○
Excitatory Postsynaptic Currents and Potentials
Post synaptic currents and potentials are called excitatory postsynaptic currents and potentials (EPSCs and
EPSPs) if they increase the likelihood of a postsynaptic action potential occurring
Synapses at which neurotransmitter release leads to the generation of EPSPs are called excitatory
synapses
○
○
If the reversal potential of the ligand gated ion channels carrying the postsynaptic current is more positive than
the action potential threshold, the postsynaptic potential facilitates action potential generation and is excitatory
○
Examples for excitatory synapses:
Glutamatergic synapses in the CNS (contain sodium and potassium permeable glutamate receptors)
○
Neuromuscular junctions (contain sodium and potassium permeable acetylcholine receptors)
○
○
Inhibitory Postsynaptic Currents and Potentials
Postsynaptic currents and potentials are called inhibitory postsynaptic currents and potentials (IPSCs and IPSPs)
if they decrease the likelihood of a post synaptic action potential occurring
○
Synapses at which neurotransmitter release leads to the generation of IPSPs are called inhibitory synapses
○
If the reversal potential of the ligand-gated ion channels carrying the postsynaptic current is more negative than
the action potential threshold, the postsynaptic potential inhibits action potential generation
○
If Erev<Vmthe IPSP inhibits action potential generation by hyperpolarizing the membrane potential
○
If Erev>Vmthe IPSP is depolarizing but tends to keep the membrane potential at a value more negative than the
action potential threshold (Erev) making it harder for adjacent excitatory synapses to elicit an action potential.
Shunting inhibition
Depolarizes but never actually creates an action potential
○
○
Ion channels open at the synapse and the membrane would depolarize but it can only do so until the
reversal potential of these channels, it cannot be more potential otherwise there will be no net flow of ions
across the membrane
○
If you have an inhibitory synapse open that has a reversal potential above the membrane potential, it is
still inhibitory
Shunting inhibition
○
○
○
Example for inhibitory synapses:
GABAergic synapses in the CNS (contain chloride permeable GABA receptors)
○
○
Properties of Transmission at Chemical Synapses: Comparison with electrical synapses
Electrical Synapse
Chemical Synapse
Directionality of
transmission
Frequently bidirectional - can depolarize both
neuron A and neuron B
Unidirectional (transmission from pre to
postsynaptic neuron) - post synaptic
neuron cannot talk in the reverse
Synaptic delay
.1ms or less
.5-2ms
Direction of post
synaptic potential
change
Same as presynaptic potential change. Always
the same, if you have a depolarization in the
presynaptic neuron then you get a depolarization
in the post synaptic neuron
Either hyperpolarizing or depolarizing:
Depends on Vmand Erev of postsynaptic
ligand-gated ion channels
Amplitude of
postsynaptic
potential change
Fraction of presynaptic potential change; slow
potential changes transmitted better.
Depends on Vm, Erev of ion channel
involved, and on number and conductance
of opened channels
Transmission of
presynaptic
subthreshold activity
Yes
No; transmission requires presynaptic
action potential
Synaptic delay can be larger if it involves metabotropic receptors and modulation of second messenger
cascades
○
Exception to this requirement: Photoreceptors and bipolar cells in the retina and hair cells in the inner ear
release neurotransmitter in response to graded receptor potentials
○
Chemical synapses allow for much more alteration in post synaptic potential relative to pre synaptic
potential
Electrical synapses always have a 1 to 1 ratio from post synaptic to pre synaptic
○
○
Stefan Krueger
○
Monday mornings
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/
Electrical and Chemical Synapse
October)19,)2015
1:47)PM
Document Summary
Synapse: specialized zone of contact at which one neuron communicates with another. Points of contact between neurons that serve for communication - there are an incredible amount of synapses in the brain. The average neuron receives 1000 synapses ( some neurons in the cerebellum: 10,000 synaptic contacts) Number of synapses in the human brain: 1015 - 1016. Electrical synapses: junctions between neurons permitting direct, passive flow of electrical current. Not as common - they big channels between two connective neurons and they can transmit lots. Direct link for ion transport and this will result in the communication of electrical synapse without the transduction into chemical synapse. Big channels between two connective neurons and can transmit all ions - direct link for ion transport which will result in communication of electrical signal without transducing them into chemical signals. Chemical synapses: junctions between neurons that communicate via the secretion of neurotransmitters. This is the manipulation of electrical signals into the chemical release.
