Transcript Neuron Structure and Function

Neural Zones
How Neurons connect
The Synapse
• A functional connection between surfaces
• Signal transmission zone
• Synapse – synaptic cleft, presynaptic cell, and
postsynaptic cell
• Synaptic cleft – space in between the presynaptic and
postsynaptic cell
• Postsynaptic cell – neurons, muscles, and endocrine
glands
• Neuromuscular junction – synapse between a motor
neuron and a muscle
The Synapse
• Axon terminal: found in motor neurons
• Axon varicosities: ie swellings. Arranged like beads on a string and
contain neurotransmitter containing vesicles
• En passant synapse: CNS. Consists of a swelling along the axon
• Spine synapse: presynaptic cell connects with a dendritic spine on
the dendrite of the postsynaptic cell
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The Synapse
• Axodentritic: between axon terminal of one neuron and the dendrite
of another
• Axosomatic: between the axon terminal of one neuron and the cell
body of another
• Dendrodendritic: between dendrites of neurons (often are electricla
synapses)
• Axoaxonic: between an axon terminal of a presynatpic neuron and
the axon of a postsynaptic neuron.
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Diversity of Signal Conduction
So far:
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Electrotonic
Action potentials
Saltatory conduction
Chemical and electrical synapses
Diversity of Synaptic Transmission
Electrical and Chemical Synapses
Electrical synapse
Chemical synapse
Rare in complex animals Common in complex
animals
Common in simple
Rare in simple animals
animals
Fast
Sloooooow
Bi-directional ↔
Unidirectional →
Postsynaptic signal is
similar to presynaptic
Excitatory
Postsynaptic signal can
be different
Excitatory or inhibitory
Electrical synapses
cells connect via gap junctions
- membranes are separated by 2 nm
- gap junctions link the cytosol of two cells
- provide a passageway for movement of very
small molecules and ions between the cells
- gap junction channels have a large conductance
- NO synaptic delay (current spread from cell to cell is instantaneous)
- important in some reflexes
- chemical synapses do have a significant delay ie slow
- commonly found in other cell types as well i.e. glia
- can be modulated by intracellular Ca2+ , pH, membrane voltage,
calmodulin
- clusters of proteins that span the gap such that ions and small
molecules can pass directly from one cell to another
More about electrical synapses
cells connect via gap junctions
- made up of 6 protein subunits arranged around a central pore, made
up of the connexin protein
- the two sides come together to make a complete unit of 12 proteins
around the central pore
Chemical Synapse Diversity
Vary in structure and location
Chemical Synapse
• most common type of synapse
• electrical signal in the presynaptic cell is communicated to the
postsynaptic cell by a chemical (the neurotransmitter)
• separation between presynaptic and postsynaptic membranes is
about 20 to 30 nm
• a chemical transmitter is released and diffuses to bind to receptors
on postsynaptic side
• bind leads (directly or indirectly) to changes in the postsynaptic
membrane potential (usually by opening or closing transmitter
sensitive ion channels)
• the response of the neurotransmitter receptor can depolarizes
(excitatory postsynaptic potential; epsp) or hyperpolarizes (inhibitory
postsynaptic potential; ipsp) the post-synaptic cell and changes its
activity
• significant delay in signal (1 msec) but far more flexible than
electrical synapse
More about chemical Synapses
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Some types of chemical synapse include
Excitatory - excite (depolarize the postsynaptic cell
Inhibitory - inhibit (hyperpolarize the postsynaptic cell)
Modulatory - modulates the postsynaptic cells response to other
synapses
General sequence of events
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General sequence of events
1. Nerve impulse arrives at presynaptic terminal
2. Depolarization causes voltage-gated Ca 2+ channels to open
- increases Ca 2+ influx, get a transient elevation of internal Ca 2+
~100 mM
3. Vesicle exocytosis
- increase in Ca 2+ induces fusion of synaptic vesicles to membrane
- vesicles contain neurotransmitters
4. Vesicle fusion to membrane releases stored neurotransmitter
5. Transmitter diffuses across cleft to postsynaptic side
6. Neurotransmitters bind to receptor either:
i) ligand-gated ion channel or
ii) receptors linked to 2nd messenger systems
7. Binding results in a conductance change
- channels open or close or
- binding results in modulation of postsynaptic side
Cont…….
General sequence of events
8. Postsynaptic response
- change in membrane potential (e.g. muscle contraction in the case
of a motorneuron at a neuromuscular junction)
9. Neurotransmitter is removed from the cleft by two mechanisms
i) transmitter is destroyed by an enzyme such as acetylcholine
esterase
ii) transmitter is taken back up into the presynaptic cell and recycled
e.g. - acetylcholine esterase, breaks down acetylcholine in cleft,
choline is recycled back into the presynaptic terminal
Neurotransmitters
Characteristics
• Synthesized in neurons
• Released at the presynaptic cell following
depolarization
• Bind to a postsynaptic receptor and causes
an effect
Neurotransmitters, Cont.
More than 50 known substances
Categories
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Amino acids
Neuropeptides
Biogenic amines
Acetylcholine
Miscellaneous …..
Neurons can synthesize many kinds of
neurotransmitters
Neurotransmitters
Neurotransmitters cont.
Neurotransmitter Action
Inhibitory neurotransmitters
• Cause hyperpolarization
• Make postsynaptic cell less likely to generate
an AP
Excitatory neurotransmitters
• Cause depolarization
• Make postsynaptic cell more likely to generate
an AP
Amount of Neurotransmitter
Influenced by AP frequency which
influences Ca2+ concentration
Control of [Ca2+]
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Open voltage-gated Ca2+ channels  [Ca2+]
Binding with intracellular buffers  [Ca2+]
Ca2+ ATPases  [Ca2+]
High AP frequency  influx is greater than
removal  high [Ca2+]  many synaptic
vesicles release their contents  high
[neurotransmitter]
Signal Strength
Influenced by neurotransmitter amount and
receptor activity
Neurotransmitter amount: Rate of release
vs. rate of removal
• Release: due to frequency of APs
• Removal
• Passive diffusion out of synapse
• Degradation by synaptic enzymes
• Uptake by surrounding cells
• Receptor activity: density of receptors on
postsynaptic cell
Ca2+ Regulates Neurotransmitter Release
Graded Potentials via Neurotransmitters
• Vary in magnitude depending on the
strength of the stimulus
• e.g., more neurotransmitter  more ion
channels will open
• Can depolarize (Na+ and Ca2+ channels)
or hyperpolarize (K+ and Cl- channels) the
cell
Graded Potentials
Graded Potentials Travel Short Distances
Neurotransmitter Receptor Function
Ionotropic
• Ligand-gated ion channels
• Fast
• e.g., nicotinic ACh
Metabotropic
• Channel changes shape
• Signal transmitted via
secondary messenger
• Ultimately sends signal to
an ion channel
• Slow
• Long-term changes
Second Messenger again
• When activated by a ligand the catalytic
domain starts a phosphorylation cascade
• Named based on the reaction catalyzed
Second Messengers to know
Neurotransmitter receptors
Different types of neurotransmitter receptors
Functional Type
Ligand
Ion Channel
Excitatory Receptors
Acetylcholine
Glutamate
Glutamate
Serotonin
Na+/K+
Na+/K+; Ca2+
Na+/K+
Na+/K+
Inhibitory Receptors
Aminobutyric acid, GABA
Glycine
ClCl-
Removal of Neurotransmitter
a)
broken down by enzyme
- acetylcholine esterase breaks down acetylcholine in the
synaptic cleft
- many nerve gases and insecticides work by blocking
acetylcholine esterase – Yikes!
- prolongs synaptic communication
b)
recycled by uptake
- most neurotransmitters are removed by Na+/neurotransmitter
symporters
- due to a specific neurotransmitter transporter
- recycled by uptake into presynaptic terminal or other cells
(glial cells will take up neurotransmitters)
c)
diffusion: simple diffusion away from site
Neurotransmitters - stages
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Synthesis
- all small chemical neurotransmitters are made in the nerve
terminal
- responsible for fast synaptic signalling
- synthetic enzymes + precursors transported into nerve terminal
- subject to feedback inhibition (from recycled neurotransmitters
- can be stimulated to increase activity (via Ca2+ stimulated
phosphorylation)
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Packaging into vesicles
- neurotransmitters packaged into vesicles
- packaged in small "classical" vesicles
- involves a pump powered by a pH gradient between outside and
inside of vesicle
- pump blocked by drugs and these block neurotransmitter release
Presynaptic vesicles
Two groups
i) low molecular weight, non-peptide
e.g. acetylcholine, glycine, glutamate
ii) neuropeptide (over 40 identified so far and counting…..)
Presynaptic vesicles
• There are 2 types of secretory vesicles
• We will only talk about small chemical synaptic vesicles
• Neuropeptides are made and packaged in the cell body and
transported to synapse)
• Small chemical neurotransmitter vesicles
• responsible for fast synaptic signaling
• store non-peptide neurotransmitters,
e.g. acetylcholine, glycine, glutamate
• enough vesicles in the typical nerve terminal to transmit a few
thousand impulses
• exocytosis only occurs after an increase of internal Ca 2+ (due to
depolarization) and at active zones (regions in the presynaptic
membrane adjacent to the cleft)
Presynaptic vesicles
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Vesicle Exocytosis
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A group of 6 to 7 proteins work together to respond to Ca 2+ influx
and regulate vesicle fusion
after exocytosis the synaptic vesicle membranes are
reinternalized by endocytosis and reused (reloaded with
neurotransmitter by a transmitter transporter system)
vesicles are also transported from the cell body to the nerve
terminal
- transmitter is synthesized in the terminal and loaded into the
vesicles
- enzymes and substrates necessary are present in the terminal
- i.e. acetylcholine, acetyl-CoA + choline used by choline
acetyltransferase
Vesicle Exocytosis
non-peptide transmitters
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exocytosis only occurs after an increase of internal Ca 2+ (due to
depolarization)
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at active zones (regions in the presynaptic membrane adjacent to
the synaptic cleft)
peptide-transmitters (same as for non-peptide transmitters except:)
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exocytosis is NOT restricted to active zones
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exocytosis is triggered by trains of action potentials
SNARE hypothesis
The SNARE Hypothesis for Transport Vesicle Targeting and Fusion
SNARE is an acronym for SNAP receptor (SNAP stands for soluble Nethylmaleimide-sensitive factor attachment proteins).
SNARES are involved in the mediation of protein transport between
various plant organelles by small membrane vesicles.
Two families:
i) V-SNARE - vesicle membrane proteins
ii) T-SNARE - target membrane proteins
SNARE hypothesis
1. Vesicle docking occurs between the VSNARE and T-SNARE proteins
2. The combined proteins act as a receptor for
an ATPase that utilizes ATP to generate the
"docked" form
3. One of the proteins is a Ca2+ sensor such
that when Ca2+ enters the synapse the
vesicle fuses with the plasma membrane and
releases its contents
4. The membrane and proteins are then
recycled through endocytosis (clatharin coat
and dynamin etc.) and reused.
Synaptic Plasticity
• Change in synaptic function in response to patterns of
use
• Synaptic facilitation –  APs   neurotransmitter
release
• Synaptic depression –  APs   neurotransmitter
release
• Post-tetanic potentiation (PTP) – after a train of high
frequency APs   neurotransmitter release
Long-term potentiation
Diversity of Signal Conduction
So far:
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Electrotonic
Action potentials
Saltatory conduction
Chemical and electrical synapses
Also:
• Shape and speed of action potential
• Due to diversity of Na+ and K+ channels
Ion Channel Isoforms
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Multiple isoforms
Encoded by many genes
Variants of the same protein
Voltage-gated K+ channels are highly diverse (18 genes
encode for 50 isoforms in mammals)
Na+ channels are less diverse (11 isoforms in mammals)
Channel Density
Higher density of voltage-gated Na+
channels
 Lower threshold
 Shorter relative refractory period
Voltage-Gated Ca2+ Channels
• Open at the same time or instead of
voltage-gated Na+ channels
• Ca2+ enters the cell causing a
depolarization
• Ca2+ influx is slower and more sustained
• Slower rate of APs due to a longer
refractory period
• Critical to the functioning of cardiac muscle
Chemical synapses: post-synaptic mechanisms
Postsynaptic Membranes and ion channels
Ligand gated ion channels – a review
a. Resting K+ channels: responsible for generating the resting potential
across the membrane
b. Voltage- gated channels: responsible for propagating action potentials
along the axonal membrane
Two types of ion channels in dendrites and cell bodies are responsible for
generating electric signals in postsynaptic cells.
c. Has a site for binding a specific extracellular neurotransmitter
d. Coupled to a neurotransmitter receptor via a G protein.
More things to know about Ion channels
All the ion channels in question have a common feature
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A pore that allows the ion(s) in question to flow across the lipid bilayer
The pore is specific to a certain ion or ions
• Leak K+ channel only allows K+ ions to flow across the membrane
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Examples: Acetylcholine (ACH) receptor allows Na+ to flow and the
glycine receptor allows Cl- to flow through the channel
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Ligand gated ion channels are different than voltage-gated ion
channels in that they are chemically gated ie via neurotransmitters
Binding a small chemical triggers the opening of the ion channel
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i) Na+ channels - excitatory (generates an excitatory postsynaptic
potential)
ii) Cl- channels - inhibitory (generates an inhibitory postsynaptic
potential)
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Important: The specificity of a transmitter response is a function of the
receptor type NOT the transmitter itself. (i.e. Ach can be excitatory
when binding to one type of AchR (NMJ)) and inhibitory when binding
to another type of receptor
Acetylcholine
Primary neurotransmitter at the vertebrate
neuromuscular junction
Acetylcholine – general info
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Motor neuron transmitter at the
neuromusccular junction (NMJ) in
vertebrates
Present in brain (10% of synapses)
Packaged in high numbers in vesicles
1,000 to 10,000 molecules per vesicle at
the NMJ
Like all small chemical transmitters Ach is
synthesized and packaged into vesicles in
the synapse
The NMJ pre-synaptic side is packed full of
vesicles in the axon terminal
Many vesicles are released per action
potential to ensure a large safety margin so
that the muscle fiber (i.e. the postsynaptic
cell) will depolarize to beyond threshold.
Acetylcholine – receptor
• Officially called the nicotinic ACH receptor
(nAChR) because nicotine binds to this
receptor and activates it
• Ligand gated ion channel
• has a depolarizing effect because Na+ is
the dominant ion through these channels
Acetylcholine – receptor
• generates an excitatory postsynaptic potential which at the NMJ
(motor end plate) is often called an "end plate potential“
EPP - end plate potential
Aka Excitatory Junctional Potential (EJP)
End plate potentials (EPPs) evoked by stimulation of a motor neuron are
normally above threshold and therefore produce an action potential
in the postsynaptic muscle cell.
nACHR – a closer look
• Most of the mass of the protein protrudes from the outer (synaptic)
surface of the plasma membrane
• The M2 alpha helix (red) in each subunit is part of the lining of the ion
channel
• Aspartate and glutamate side chains at both ends of each M2 helix
form two rings of negative charges that help exclude anions from and
attract cations to the channel. The gate, which is opened by binding of
acetylcholine, lies within the pore.
Aspartate
The Neuromuscular junction
The Neuromuscular junction
The Neuromuscular junction
• Arrival of an action potential at the terminus of a presynaptic motor
neuron induces opening of voltage-gated Ca2+ channels
• subsequent release of acetylcholine, which triggers opening of the
ligand-gated nicotinic receptors in the muscle plasma membrane
• The resulting influx of Na+ produces a localized depolarization of the
membrane
• leading to opening of voltage-gated Na+ channels and generation of an
action potential
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Synapses in the brain or central nervous system (CNS)
• A single synapse on a target is seldom found in brain
• Large neurons in the brain typically receive many inputs (1000 to
80,000 per cell)
• The inputs are integrated in the receiving neuron such that a "decision"
is made to pass on the information onto other cells
- this "decision" is often whether or not to generate an action potential
• each synaptic input usually only gives only a small depolarization, so
many inputs must cooperate (summate) to reach threshold to fire an
action potential
EPSP
An excitatory impulse, an excitatory post-synaptic potential raises the
membrane potential above rest
1.An excitatory impulse at a synapse on the soma causes a depolarization
of the whole soma including the beginning of the axon. The beginning of
the axon is also known as the spike initialization zone or axon hillock and
is packed with Na+ channels, an epsp of +15 to +20 mV triggers an action
potential in the zone
2. Due to the absence of voltage-gated Na+ channels in the soma and
dendrite of most neurons it is very unlikely that an action potential will be
generated in these regions
IPSP
•An inhibitory impulse is called an ipsp (inhibitory post-synaptic potential)
and lowers the membrane potential below rest (hyperpolarizes)
•Synaptic transmission triggers the opening ligand gated Cl- channels or
indirectly through other mechanisms the opening of K+ channels
•Cl- flows into the cell
•K+ flows out of the cell
•Both increase the negative charge within the cell, hyperpolarizes the
soma
•Brings membrane potential further away from threshold and so it is harder
to trigger an action potential therefore inhibitory
•An ipsp on the dendrite will have less effect due to current loss than an
ipsp in the soma
CNS
Major ligand gated ion channels and their neurotransmitters
Glutamate - amino acid
•Most common excitatory neurotransmitters in central nervous system
•Neurotransmitter of NMJ in invertebrates (locust, giant axon of squid)
•Glutamate receptor - at least 3 different ligand gated ion channel receptors
for glutamate - all generate epsps as Na+ is the dominant ion that flows after
the channel is open
GABA - aminobutyric acid
•Major inhibitory neurotransmitter in the brain
•In some areas of cortex 1 in 5 neurons are GABAergic
•GABA receptors
- again many different types of receptors
- the more common GABA receptors are Cl - channels
- usually inhibitory causes an inhibitory postsynaptic potential (IPSP)
- reversal potential is the same as ECl - usually around - 70 mV
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Note: reversal potential is synonymous with equilibrium potential
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CNS
Glycine - simplest amino acid
•Major inhibitory neurotransmitter in the brainstem and spinal cord
•Glycine Receptor
- major receptor is a Cl - channel
- inhibitory
- like GABA receptor in that usually causes IPSPs
- blocked by strychnine (rat poison) which literally causes convulsions
and death as now the motor neurons are not inhibited and the
muscles contract without control. Yikes!
Cable properties again
• Dendrites extend 0.5 to 1 mm in all directions from soma and receive
signals from a large area
• 80-90% of all presynaptic terminals terminate on dendrites
• Most can't produce action potentials (too few or no Na+ channels)
• Transmit current by passive spread down dendrites to the soma
• Therefore the membrane potential decreases as move along dendrite
due to current loss thanks to our friends ri, rm and cm
• Dendrites have no voltage gated Na+ channels and cell bodies ie soma
have little or no voltage-gated Na+ channels current flow is solely
dependent on the Cable Properties of the dendrites and soma
Things to remember
• 1) loss of current across membrane (leaky membranes)
• dependent on the internal resistance (ri) and the membrane resistance
(rm)
• the length or space constant describes this property
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  rm / ri
• 2) loss of current (charge) due to capacitance properties of the
membrane
• cell membrane acts as a capacitor
• it takes time and current (charge) to charge the membrane capacitor
• the time constant describes this effect
τ = Rm x Cm
• details are in the lecture on cable properties 
Summation - CNS
•The postsynaptic effects of most synapses in the brain are not as large as
those at the neuromuscular junction
•In the CNS the postsynaptic potentials are usually far below the threshold
for generating postsynaptic action potentials
•Neurons in the central nervous system are typically innervated by
thousands of synapses, and the postsynaptic potentials produced by each
active synapse can summate together (in space and in time) to bring the
membrane to threshold for firing an action potential
Motor neurons and summation
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Each motor neuron synapses with multiple muscle fibers
The motor neuron and the fibers it contacts defines the motor unit
Summation
Summation of multiple epsps to bring the membrane potential to threshold
for an action potential.
Summation
A microelectrode records the postsynaptic potentials produced by the
activity of two excitatory synapses (E1 and E2) and an inhibitory synapse (I)
Electrical responses to synaptic activation
1. Stimulating either excitatory synapse (E1 or E2) produces a subthreshold
EPSP, whereas stimulating both synapses at the same time (E1 + E2)
produces a suprathreshold EPSP that evokes a postsynaptic action
potential
2. Activation of the inhibitory synapse alone (I) results in a hyperpolarizing
IPSP
3. Summing this IPSP with the EPSP produced by
one excitatory synapse (E1 + I) reduces the
amplitude of the EPSP, while summing it with the
suprathreshold EPSP produced by activating
synapses E1 and E2 keeps the postsynaptic
neuron below threshold, so that no action
potential is evoked.
Summation