Chapter 4: Neural Conduction (Membrane Potentials)
4.1 The Neuron's Resting Membrane Potential
A. Recording the Membrane Potential
1. intracellular microelectrode
2. oscilloscope
- Two electrodes are used in recording the membrane potential: an extracellular
electrode and an intracellular electrode.
- The extracellular electrode tip is positioned outside the neuron while the tip of the
intracellular electrode is positioned in the neuron. The intracellular electrode must
therefore be small enough to pierce the neural membrane without destroying the
neuron; the tip of a microelectode is 1 thousandth of a mm.
- An oscilloscope is a device that shows the difference in the electrical potential at the
two electrode tips over time (as vertical displacements of a glowing spot of light that
sweeps across a flourescent screen).
B. Resting Membrane Potential
- is about -70 mV. That is, the potential inside the neuron is 70 mV less than that
outside the neuron. Neuron's in the resting state are said to be polarized because the
ratio of negative to positive charges is greater inside the neuron than outside.
- If -70 mV is polarized then what is a - 65 mV membrane potential and a -72 mV
potential? (depolarization; hyperpolarization)
C. The Ionic Basis of the Resting Potential
1. ions (Na+, K+ , Cl-, A--)
2. differential permeability
- The membrane potential results from the distribution of positively and negatively
charged particles called ions. There are 4 kinds of ions that contribute to the resting
potential: Sodium (Na+), potassium (K+), chloride (Cl-), and negatively charged
protein ions sometimes called Anions (A--).
- The concentration of Na+ and Cl- ions are greatest outside of the resting cell, whereas
the concentrations of K+ is greatest inside the cell and negatively charged protein
ions which are synthesized inside the neuron are trapped there.
- The neuronal membrane is porous (i.e., contains ion channels) and allows certain
ions to pass in and out of the cell more readily than others. This passive property of
the cell membrane is called differential permeability and contributes to the polarized
resting potential. For example, both K+ and Cl- ions readily diffuse through the neural
membrane; Na+ ions diffuse with more difficulty and anions cannot diffuse at all.
3. two homogenizing forces opposed to the resting potential
a) random motion (concentration gradient)
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b) electrostatic pressure
- random motion (concentration gradient) distributes particles from areas of high
concentration to areas of low concentration.
- electrostatic pressure attempts to evenly distribute positive and negative ions
through repulsion of like charges and attraction of opposite charges.
4. sodium-potassium pump
- In addition to differential permeability, Hodgkin and Huxely (1950) showed that an
active process also contributes to the uneven distribution of particle ions inside and
outside of the neuron.
- They calculated the electrostatic charge that would be required to offset the pressure
for Cl-, Na+, and K+ to move down their concentration gradients.
- The calculated value for Cl- ions was -70 mV (the same as the resting potential). So,
the uneven distribution of Cl- ions outside the neuron is maintained because the 70
mV force driving Cl- into the cell is met with an equal force of electrostatic pressure
driving it out.
- For K+ ions Hodgkin and Huxley calculated that - 90 mV of electrostatic pressure was
required to prevent K+ from leaving the cell, 20 mV more than the resting potential.
Therefore, some K+ must leak out of the neuron.
- For Na+, the calculated values were 70 mV of electrostatic pressure and 50 mV of
pressure from the concentration gradient, both of which drive Na + into the cell. So,
although it is difficult for Na+ to pass through the neural membrane, some of these
ions should leak in.
- Hodgkin and Huxley concluded that there must be some active mechanism in the
membrane to counteract the influx of Na+ and the efflux of K+.
- The active transport of Na+ out of the neuron and K+ ions into them are not
independent processes; there is an energy-consuming mechanism located in the cell
membrane that continuously exchanges 3 Na+ ions inside the neuron for 2 K+ ions
outside. This mechanism is refered to as the sodium-potassium pump.
4.2 The Generation and Conduction of Postsynaptic Potentials - When neurotransmitter molecules bind to postsynaptic receptors, they have one of
two effects: depolarization or hyperpolarization.
- Depolarizations are called Excitatory postsynaptic potentials (or EPSPs) because
they increase the likelihood that the neuron will fire; Hyperpolarizations are called
Inhibitory postsynaptic potentials (IPSPs) and decrease the likelihood that the
neuron will fire. Both events are graded potentials because the strength of their
effects are proportional to the intensity of the signal.
- EPSPs and IPSPs travel passively through the neuron like an electrical signal travels
through a cable. This results in rapid transmission that is decremental - i.e., the
signal gets weaker (decreases in amplitude) the farther it travels.
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4.3 The Integration of Postsynaptic Potentials and the Generation of
Action Potentials
- Each neuron receives thousands of synaptic contacts which produce graded
potentials. Whether or not a neuron fires depends on the summation of the signals
that reach the axon hillock.
- The integration of graded potentials summate in two ways: temporally and spatially.
- Temporal summation refers to the combining of signals from a single synapse
across time.
- Spatial summation refers to the combination of signals from different synapses that
are located in close proximity to each other.
- If the combined stimulation results in a sufficient depolarization at the hillock then the
neuron will generate an action potential; the threshold of excitation is about -65
mV for many neurons.
What is an action potential? Lets consider some of the characteristics just mentioned
for postsynaptic potentials to get an idea.
Contrasting Potentials
Postsynaptic Potentials
1. Graded events - they come in
different sizes; often equal to the
amount of neurotransmitter.
2. Not Propagated - they travel
solely by passive cable properties.
3. Decremental - the farther they
go the weaker they get.
Action Potentials
1. All-or-none - it either occurs
or it doesn't; like firing a gun. It
is always the same size.
2. Propagated - once they begin
they travel the full length of the
axon.
3. Nondecremental - the height
of the AP when it reaches the
bouton is the same as where it
started back at the hillock.
4.4 Conduction of Action Potentials
is based on the action of voltage-gated ion channels - channels that open and close
in response to the changes in the voltage of the membrane potential.
A. Ionic Basis of Action Potentials
- rising phase: When the membrane potential at the axon hillock is reduced to the
threshold of excitation, voltage-gated sodium channels open and Na+ ions rush in the
cell driving the membrane potential from -70 to almost +50 mV.
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- This change in membrane potential causes voltage-gated potassium channels to open
and K+ ions near the membrane rush out of the cell (down its concentration gradient)
while some Cl- ions rush in. At the peak of the AP, the positive internal charge keeps
the K+ channels open as the Na+ channels close thus ending the rising phase and
begining the repolarization phase.
- repolarization phase: As K+ continues to exit the neuron there is a return to the
resting potential. The K+ channels then slowly begin to close. Since they close slowly
a bit more potassium leaves causing a brief hyperpolarization - that is a slight drop
below the normal -70 mV resting membrane potential.
- hyperpolarization is the third phase.
- The AP only involves the flow of a small amount of ions through the membrane (only
those right next to it) and therefore has little effect on the relative concentrations of
the various ions inside and outside the neuron. Therefore, the sodium-potassium
pump plays only a minor role in reestablishing the resting potential.
Sodium
channels
close
Membrane Potential (mV)
+70
+50
+30
+10
Potassium
channels
open
-10
-30
-50
Sodium
channels
open
Potassium
Channels
start to
close
-70
1
2
3
4
5
Time (milliseconds)
B. Refractory Periods
- After a neuron has fired there is a brief period during which another action potential
cannot be generated. This is called the absolute refractory period and lasts 1 to 2
milliseconds.
- This period is followed by a relative refractory period during which only higher than
normal levels of stimulation will elicit an AP.
- The refractory period:
(1) ensures that APs normally travel in one direction, called orthodromic conduction,
(since the previous portion cannot conduct the AP in the other, antidromic, direction)
and
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(2) is responsible for the fact that the rate of neural firing is related to the intensity of the
stimulation; if a neuron is bombarded with stimulation it fires and then fires again after
the absolute refractory period is over - the maximum is about 1,000 times per second.
If there is only a low level of stimulation then the neuron will only fire after both the
absolute and relative refractory periods have occurred.
C. Conduction of Action Potentials
- The conduction of APs in unmyelinated axons is nondecremental - i.e., it does not get
weaker the further it travels in contrast to EPSPs and IPSPs. This is because the
various voltage-gated ion channels are close together on the axon membrane, thus
allowing the AP to travel as a wave of excitation rather than a series of discrete
events.
- When the AP is initiated at the hillock it does travel back into the cell body and
dendrites but the sodium channels there are not voltage-activated and therefore it
travels passively in the antidromic direction.
D. Conduction in Myelinated Axons
- is faster because the AP travels passively along segments of myelin.
- the nodes of Ranvier act as boosters that recharge the AP to full strength.
- Conduction of APs in myelinated Axons is called Saltatory conduction (Saltare dance or jump)
E. The Velocity of Axonal Conduction
- is faster in myelinated axons, as just mentioned, and is faster in large-diameter axons.
- motor neurons have large diameter axons that are myelinated and some can conduct
APs at speeds of up to 100 meters per second (224 mph). In contrast, small
unmyelinated axons conduct APs at about 1 meter per second (2 mph).
F. Conduction in Neurons without Axons
- neurons without axons cannot conduct APs. Such interneurons conduct only graded
potentials.
Chapter 4: Synaptic Transmission
4.5 Synaptic Transmission: Chemical Transmission of Signals from
One Neuron to Another
Structure of Synapses
- some anatomical features of the synapse (fig. 4.9).
a) synaptic vesicles - contain neurotransmitter substance; located near
presynaptic membrane.
b) golgi apparatus (and cisternas) - are neurotransmitter packaging plants.
c) microtubules - fine "struts" found in axons and dendrites that help maintain
the cell's structure and also transport substances to and from the soma.
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d) mitochondria - are structures that extracts energy from glucose.
- types of synapses (4 mentioned)
- the two common ones are: axodendritic and axosomatic. Axodendritic synapses
include the terminal end of the axon (the synaptic button) and the dendrite, which
sometimes have small synaptic buds called dendritic spines on their surface.
Axosomatic synapses are between the axon terminal button and the cell body.
- a less common type of synapse is dendrodentritic (dendrite-to-dendrite) which are
often capable of transmission in either direction.
- another less common type is the axoaxonal synapse (axon-to-axon). Some of
these synapses mediate Presynaptic inhibition where one terminal button partially
depolarizes another so that there is less neurotransmitter to release when an action
potential activates the latter button. (contrast with postsynaptic inhibition).
- In addition to directed synapses, where the neurotransmitter release and reception
sites are close together (i.e., a small synaptic gap), there are also nondirected
synapses where the site of release is some distance from the site reception. One
example, is how varicosities or swellings along the axon release neurotransmitter that
travels through the extracellular space to distant target sites.
Synthesis, Packaging, and Transport of Neurotransmitter Molecules
- Small molecule neurotransmitters - are synthesized in the cytoplasm of the button
and packaged in synaptic vesicles by the golgi apparatus. The neurotransmitter filled
vesicles are then stored near areas of the presynaptic membrane.
- Large molecule neurotransmitters - are peptides (chains of amino acids) and are
synthesized in the cell body (like other proteins) by ribosomes. Peptide transmitters
are packaged in vesicles by the cell body’s golgi complex and are transported by
microtubules to the terminal buttons at a rate of about 40 cm/day (axoplasmic
transport). The vescicles containing peptides are larger than those containing smallmolecule neurotransmitters and are located further away from the presynaptic
membrane. Frequently, a terminal button may contain both a peptide and a small
molecule neurotransmitter, a situation referred to as coexistence.
Release of Neurotransmitter Molecules (T#20, T#16ab)
- When an action potential reaches the button it causes voltage-activated calcium
channels to open and the influx of calcium causes the vesicles to fuse with the
presynaptic membrane and release neurotransmitter substance into the synaptic cleft
(this is called exocytosis).
- There is one important difference between the release of small molecule
neurotransmitters and peptides. Small molecule neurotransmitters are released in
brief pulses each time an AP triggers the infulx of calcium. Peptide neurotransmitters
are released gradually over time in response to general increases in the level of
intracellular calcium.
The Activation of Receptors by Neurotransmitter Molecules
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- Neurotransmitter molecules bind to postsynaptic receptors which are proteins that
contain binding sites for a particular neurotransmitter.
- There are typically several receptor subtypes (located in different brain areas) for a
particular neurotransmitter. The receptor subtypes respond to the neurotransmitter in
different ways.
- Neurotransmitter binding influences the postsynaptic neuron in one of two ways
(depending on whether the receptor is linked to an ion-channel or a G-protein).
- Ion-channel linked receptors are components of chemically-activated ion
channels in the postsynaptic membrane. When a neurotransmitter binds to the
receptor the ion channel opens or closes.
- For example, a neurotransmitter might have an excitatory effect (i.e., cause an EPSP)
by binding to a receptor that opens sodium channels, the influx of sodium would result
in depolarization. An inhibitory effect (IPSP) could occur by opening potassium or
cloride channels.
- G-protein linked receptors are more common than ion-channel linked receptors and
their effects are slower, longer-lasting, more diffuse, and more varied.
- This type of receptor is composed of a long protein chain that winds its way in and out
of the cell several (7) times and is located next to a G (guanine-sensitive) protein.
- When a neurotransmitter binds to this receptor a subunit of the G-protein breaks away
and one of two things happens. The subunit may move along the inside portion of the
membrane to a nearby ion channel and cause an EPSP or IPSP. Or, it may trigger
the synthesis of a chemical called a second messenger which does one of three
things.
- Second messengers can: (1) bind to an ion channel and induce a postsynaptic
potential, (2) influence the metabolic activity of the cell, or (3) enter the nucleus and
bind to DNA to influence gene expression.
- Small molecule neurotransmitters are typically found in directed synapses and activate
either ion channel linked receptors or G-protein linked receptors that act directly on
ion channels.
- In contrast peptide neurotransmitters are frequently found at nondirected synapses
and are therefore released difusely in the extracellular fluid where they bind to Gprotein linked receptors that act through second messengers.
- The function of small molecule neurotransmitters is the transmission of rapid and brief
messages while the function of peptides appears to be the transmission of slow,
diffuse and long-lasting signals.
Reuptake, Enzymatic Degradation, and Recycling
- Reuptake, which is the more common form of deactivation mechanism,
refers to the process where neurotransmitter substance is quickly drawn back (in less
than one hundredth of a second) into the presynaptic terminal after release in the
synapse.
- Enzymatic degradation occurs when an enzyme breaks down a neurotransmitter into
a simpler product (sometimes a precursor) that is frequently reabsorbed in the
terminal button and used to synthesize more of the transmitter.
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- recycling in this section refers to the construction of synaptic vesicles (by the Golgi
complex) from excess portions of terminal button membrane floating in the cytoplasm.
4.6 The Neurotransmitters
- There are 4 classes of small molecule neurotransmitters: (1) the amino acids, (2) the
monoamines, (3) the recently discovered soluble gases, and (4) acetylcholine. In
addition there is one class of large molecule neurotransmitters: the neuropeptides.
- Most neurotransmitters are either excitatory or inhibitory, but there are some instances
where a single neurotransmitter may have an excitatory effect at one receptor subtype
and an inhibitory effect at another.
Amino acid Neurotransmitters
- Include glutamate, aspartate, glycine, and gamma-aminobutyric acid (GABA).
- These neurotransmitters are found in most of the fast-acting, directed synapses of the
CNS.
- Glutamate is most prevalent excitatory neurotransmitter in CNS.
- GABA is the most prevalent inhibitory neurotransmitter in CNS.
Monoamines
- Are synthesized from a single amino acid, are slightly larger than amino acid
neurotransmitters and typically have more diffuse effects.
- Monoamines are produced by neurons in the brain stem and are released from axonal
varicosities (swellings) into the extracellular fluid.
- There are 4 monoamines: dopamine, norepinephrine, epinephrine and serotonin.
- The first 3 are synthesized from the amino acid tyrosine and are classified as
catecholamines; serotonin (also called 5-hydroxytryptamine or 5-HT) is synthesized
from the amino acid tryptophan and is classified as an indolamine.
- Enzymes convert tyrosine to L-DOPA which is the precursor of Dopamine. Additional
enzymes convert dopamine to norepinephrine, and norepinephrine to epinephrine.
Norepinephrine is also called noradrenaline, and epinephrine is also called
adrenaline (thus the terms noradrenergic and adrenergic).
Soluble-Gas Neurotransmitters
- Were only recently discovered and, so far, include nitric oxide and carbon
monoxide.
- The soluble-Gases do not act like other neurotransmitters; immediately after they are
produced in the neural cytoplasm they quickly diffuse through the cell membrane
(because they are lipid soluble) into the extracellular fluid and then into nearby cells.
- Once in other cells they stimulate the production of second messengers and are
quickly broken down. They only exist for a few seconds and are therefore difficult to
study.
Acetylcholine
- Is a small-molecule neurotransmitter but is not based on an amino acid. It is created
by adding an acetyl group to a choline molecule.
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- Acetylcholine is the neurotransmitter at the neuromuscular junction and at most
synapses in the autonomic nervous system. It is deactivated by the enzyme
acetylcholinesterase in the synapse.
Neuropeptides
- Are putative neurotransmitters, i.e., they are suspected to function as
neurotransmitters. There are approximately 50 neuropeptides. Many neuropeptides
were first studied as hormones and then later found in neurons.
- One class of neuropeptides, the endorphins (or endogenous opiates) have an
interesting history. In the mid 70’s the receptor where opiate drugs have their effect
was discovered. They were called opiate receptors and several scientists logically
deduced that there must be an endogenous substance that activates these receptors.
- Subsequently, several endogenous opiate-like substances were identified along with
several receptor subtypes. These substances activate neural systems involved in
analgesia (pain supression) and mediate the experience of pleasure, which is
probably why they are addictive.
- Neuropeptides are often referred to as neuromodulators because they are thought to
adjust the sensitivity of populations of cells to the fast-acting signals of directed
synapses.
4.7 Pharmacology of Synaptic Transmission
- Drugs have two effects: they can facilitate synaptic activity of a particular
neurotransmitter, in which case they are said to be agonists, or they can inhibit
synaptic activity and are called antagonists.
How Drugs Influence Synaptic Transmission
7 steps in neurotransmitter action (figure 4.18)
1) synthesis in cytoplasm (influenced by enzymes)
2) storage in synaptic vesicles
3) breakdown of neurotransmitter that leaks from vesicles - enzymes destroy
neurotransmitter that leaks out of vesicles
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4) exocytosis - release of neurotransmitter
5) inhibitory feedback - inhibit further release by stimulating presynaptic autoreceptors
6) postsynaptic activation - bind to receptors on postsynaptic membrane
7) deactivation - reuptake/ enzymatic breakdown
- According to figure 4.19, agonist drugs can affect each step except #2 (storage in
vesicles), and antagonist drugs can affect all steps except #2 and #7 (deactivation).
- Antagonists that bind to postsynaptic receptors, thus blocking access of the usual
neurotransmitter, are called receptor blockers (or false transmitters).
Psychoactive Drugs: Four Examples
Cocaine (T #27)- is a potent catecholamine agonist that is highly addictive. Cocaine
blocks reuptake (step 7) of dopamine and norepinephrine, which is the primary method
of deactivation of these neurotransmitters. Therefore they have a have a prolonged
effect at postsynaptic receptors. The major psychological effects of cocaine are
euphoria, loss of appetite, and insomnia.
Benzodiazepines (chlordiazepoxide and diazepam have anxiolytic, sedative and
anticonvulsant effects). Benzodiazepines are GABA agonists that bind to one part of
the ion channel linked GABAA receptor which increases the binding of endongenous
GABA to a different part of receptor (this enhances GABA’s inhibitory effect by
increasing the influx of chloride ions). So, benzodiazepines do not mimic the action of
GABA. Benzodiazepine receptors are particularly dense in the amygdala which plays a
role in emotion.
Atropine - is an extract of the belladonna (literally beautiful lady) plant. It is a
muscarinic cholinergic receptor blocker (or false transmitter). High doses of atropine
disrupt memory.
Carare - is an extract of a certain class of woody vines. It is a cholinergic receptor
blocker that binds to the nicotinic subtype of acetylcholine receptors, which are found
at the neuromuscular junction. Thus, an injection of carare paralyzes the victim and
eventually kills them by blocking respiration.