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Physiology of the nerve:
Morphology:

Dendrites: The neural cells have five to seven process called dendrites that extended outward
from the cell body and arborize ‫تتفرع‬extensively.

Axon: It is fibrous structure that originates from a somewhat thickened area of the cell body
(the axon hillock).

Synaptic knobs: The axon divides into terminal branches, each ending in a number of synaptic
knobs. The knobs are also called (terminal buttons or axon telodendria).They contain granules or
vesicles in which the synaptic transmitters secreted by the nerve are stored.
Schwann cell:
The axons of many neurons are myelinated (i.e. they acquire a sheath of myeline, a protein-lipid
complex that is warped around the axon). Outside the CNS, the myelin is produced by Schwann cells,
found along the axon. Myeline forms when a Schwann cell warps its membrane around an axon up to
100 times.
The myeline sheath envelops the axon except at its ending and at the nodes of Ranvier (periodic 1μm constrictions that are about 1 mm apart). Some of neurons are not myelinated (un-myelinated
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neurons) i.e. are simply surrounded by Schwann cells without the warping of the Schwann cell
membrane around the axon that produces myelin.
In CNS most neurons are myelinated, but the cells that form the myelin are oligodendrogliocytes rather
than Schwann cells.
In multiple sclerosis, a crippling autoimmune disease, there is patchy destruction of myeline in the
CNS. The loss of myeline is associated with delayed or blocked conduction in the de-myelinated
axons.
Protein synthesis and axo-plasmic transport:
o
Nerve cells are secretory cells, but they differ from other secretory cells in that the secretory
zone is generally at the end of the axon, far removed from the cell body (soma).
o
All necessary proteins are synthesized in the cell body and then transported along the axon to
the synaptic knobs by the process of (axo-plasmic flow).
o
The cell body maintains the functional and anatomical integrity of the axon: if the axon is cut,
the part distal to the cut degenerates (wallerian degeneration).
Membrane potential:
Membrane potential (also trans-membrane potential or membrane voltage)
Membrane potential is the difference in electrical potential between the interior and the exterior of a
biological cell.
The membrane potential has two basic functions.
First, it allows a cell to function as a battery, providing power to operate a variety of "molecular
devices" embedded in the membrane.
Second, in electrically excitable cells such as neurons and muscle cells, it is used for transmitting
signals between different parts of a cell.
Membrane potential is a separation of opposite charge across the plasma membrane

Membrane potential is separation of charges across the membrane or to a difference in the
relative number of cations (+ ions) and anions (-ions) in the ICF and ECE.

Work must be performed (energy expended) to separate opposite charges after they have
come together.

A separation of charges across the membrane is called a membrane potential. Potential is
measured in units of volts or milli-volt.
The vast majority of the fluid in the ECF and ICF is electrically neutral. The unbalanced charges
accumulate in the thin layer along the plasma membrane
(These separated charges represent only a small fraction of the total number of charged particles
(ions) present in the ICF and ECF).
Membrane B has more potential than membrane A and less potential than membrane C
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
The term membrane potential refers to the difference in charge between the water-thin regions
of ICF and ECF lying next to the inside and outside of the membrane, respectively. The magnitude of
the potential depends on the degree of separation of the opposite charges
Membrane potential is due to difference in the concentration and permeability of key ions

All cells have membrane potential.

The cells of excitable tissues (e.g. nerve cells and muscle cells) have the ability to produce
rapid, transient changes in their membrane potential when excited (electrical signals).

The constant membrane potential present in the cells of non-excitable tissues and those of
excitable tissues when they are at rest (i.e. when they are not producing electrical signals) known as
the resting membrane potential.

The unequal distribution of a few key ions between the ICF and ECF and their selective
movement through the plasma membrane are responsible for the electrical properties of the
membrane. In the body, electrical charges are carried by ions. The ions primarily responsible for the
generation of the resting membrane potential are Na+, K+, and A- (The last refers to the large,
negatively charged (anionic) intracellular proteins). Other ions (calcium, chloride, and bicarbonate, to
name a few) do not make a direct contribution to the resting electrical properties of the plasma
membrane in most cells, even though they play other important roles in the body.
Na (meq/L)or(mmole/L)
K (meq/L) mmole/L Protein (A¯) (mmole/L)
Extra-cellular
150
5
0
Intra-cellular
15
150
65
Relative permeability
1
65
0
Note that Na* is in greater concentration in the extracellular fluid and K' is in much higher concentration
in the intracellular fluid.
Factors affecting membrane potential
1. Effects of Na –K pump on membrane potential:
About 20% of the membrane potential is directly generated by the Na+-K+ pump. ( three Na+ out
for every two K+ it transports in).
The remaining 80% is caused by the passive diffusion of K+ and Na+ down concentration gradients.
2. Effects of the movements of K alone on membrane potential: K equilibrium potential:
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The concentration gradient for K+ would tend to move this ion out of the cell), they would carry their
positive charge with them, so more positive charges would be on the outside (this is called diffusion
equilibrium).
Diffusion potential:
• A diffusion potential is the potential difference generated across a membrane because of a
concentration difference of an ion
• A diffusion potential can be generated only if the membrane is permeable to the ion.
• The size of the diffusion potential depends on the size of the concentration gradient.
• The sign of the diffusion potential depends on whether the diffusing ion is positively or negatively
charged.
• Diffusion potentials are created by the diffusion of very few ions and, therefore, do not result in
changes in concentration of the diffusing ions.
Negative charges in the form of A~ would be left behind on the inside (Remember that the large protein
anions cannot diffuse out, despite a tremendous concentration gradient.) A membrane potential would
now exist.
Equilibrium potential:
• The equilibrium potential is the diffusion potential that exactly balances (opposes) the tendency for
diffusion caused by a concentration difference. At electrochemical equilibrium, the chemical and
electrical driving forces that act on an ion are equal and opposite, and no more net diffusion of the ion
occurs
The membrane potential at EK+ is —90 mV. By convention, the sign always designates the polarity
of the excess charge on the inside of the membrane. A membrane potential of — 90 mV means
that the potential is of a magnitude of 90 mV, with the inside being negative relative to the outside. A
potential of +90 mV would have the same strength, but in this case the inside would be more positive
than the outside.
3. Effects of the movements of Na alone on membrane potential: Na equilibrium potential:
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The Na+ equilibrium potential (ENa+) would be + 60 mV.
Concurrent ‫تنافس‬Potassium and sodium effects on membrane potential
The resting potential (-70 mV) is much closer to EK+ (-90mV) than to ENa+ (+60Mv)
K+ exerts the dominant effect on the resting membrane potential because
The membrane is more permeable to K+
The membrane at rest is 100 times more permeable to K+ than to Na+ because typically the
membrane has many more channels open for passive K + traffic than for passive Na + traffic across
the membrane.
The greater the permeability of the plasma membrane for a given ion, the greater the tendency
for that ion to drive the membrane potential toward the ion's own equilibrium potential.
 The concentration gradients that exist across the plasma membrane
The ratios of these two respective ions from the inside to the outside are:
Na inside /Na outside = 0.1; K inside /K outside = 35.0
Membrane potentials in cells are determined primarily by three factors:
1) The concentration of ions on the inside and outside of the cell;
2) The permeability of the cell membrane to those ions (i.e., ion conductance) through specific ion
channels;
3) The activity of electro-genic pumps (e.g., Na+/K+ ATPase) that maintain the ion concentrations
across the membrane.
Using the Nernst equation to calculate equilibrium potentials
The Nernst equation is used to calculate the equilibrium potential at a given concentration difference
of a permeable ion across a cell membrane. It tells us what potential would exactly balance the
tendency for diffusion down the concentration gradient; in other words, at what potential would the ion
be at electro-chemical equilibrium?
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Typical charges on ions (z) would be –1 (Cl–), +1 (K+) and –2 (divalent anions: SO4 -2) and so on
Ci: Intra-cellular ion concentration (mM), Ce: Extra-cellular ion concentration (mM).
But:
Then the final equation will be:
c. Approximate values for equilibrium potentials in nerve and muscle.
Ion
Intracellular concentration Extracellular concentration Equilibrium Potential
Na+ 10-15 mM
135-145 mM
+65 mV
K+
140 mM
4 mM
-85 mV
Ca+ 100 nM
2.0-2.6 mM
+130 mV
The Goldman Equation Is Used to Calculate the Diffusion Potential When the Membrane Is
Permeable to Several Different Ions.
When a membrane is permeable to several different ions, the diffusion potential that develops
depends on three factors:
(1) the polarity of the electrical charge of each ion,
(2) the permeability of the membrane (P) to each ion, and
(3) the concentrations (C) of the respective ions on the inside (i) and outside (o) of the membrane,
and (P) is the permeability.
Thus, the following formula, called the Goldman equation or the Goldman-Hodgkin-Katz equation,
gives the calculated membrane potential on the inside of the membrane when two univalent positive
ions, sodium (Na+) and potassium (K+), and one univalent negative ion, chloride (Cl−), are involved.
Where (V: mv) is membrane potential; P: Permeability; i: concentration in; o: concentration out
Several key points become evident from the Goldman equation.
First, sodium, potassium, and chloride ions are the most important ions involved in the development
of membrane potentials in nerve and muscle fibers, as well as in the neuronal cells in the nervous
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system. The concentration gradient of each of these ions across the membrane helps determine the
voltage of the membrane potential.
Second, the quantitative importance of each of the ions in determining the voltage is proportional to
the membrane permeability for that particular ion. That is, if the membrane has zero permeability to
potassium and chloride ions, the membrane potential becomes entirely dominated by the
concentration gradient of sodium ions alone, and the resulting potential will be equal to the Nernst
potential for sodium. The same holds for each of the other two ions if the membrane should become
selectively permeable for either one of them alone.
Third, a positive ion concentration gradient from inside the membrane to the outside causes
electronegativity inside the membrane. The reason for this phenomenon is that excess positive ions
diffuse to the outside when their concentration is higher inside than outside.
The diffusion carries positive charges to the outside; but leaves the non-diffusible negative anions on
the inside, thus creating electro-negativity on the inside
Fourth, as explained later, the permeability of the sodium and potassium channels undergoes rapid
changes during transmission of a nerve impulse, whereas the permeability of the chloride channels
does not change greatly during this process. Therefore, rapid changes in sodium and potassium
permeability are primarily responsible for signal transmission in neurons, which is the subject of most
of the remainder of this chapter.
Excitation and conduction in neurons:
o
Nerve cells have low threshold for excitation.
o
The stimulus to nerve may be electrical, chemical or mechanical.
o
Two types of physiochemical distribution are produced:
1. Electro-tonic potential or graded potential or local, non-propagated potential depending
on their location, (synaptic or electro-tonic potential: resulting from a local change in
ionic conductance).
2. Action potential or Propagated potential, (or nerve impulses).
o
They are due to changes in the conduction of ions across the cell membrane.
o
The impulse is normally conducted along the axon to its termination.
Grading potential (local potential):
Graded potentials are local changes in membrane potential that occur in varying grades or degrees
of magnitude or strength. For example, membrane potential could change from -70 mV to -60 mV (a 10mV graded potential).
The stronger a triggering event, the larger the resultant graded potential:
1. The stronger the triggering event, the more gated channels that open, the greater the positive
charge entering the cell, and the larger the depolarizing graded potential at the point of origin.
2. The longer the duration of the triggering event, the longer the duration of the graded potential.
Graded potentials spread by passive current flow:
When a graded potential occurs locally in a nerve or muscle cell membrane, the remainder of the
membrane is still at resting potential. The temporarily depolarized region is called an active area.
Inside the cell, the active area is relatively more positive than the neighboring inactive areas that are
still at resting potential. Outside the cell, the active area is relatively less positive than these adjacent
areas. Because of this difference in potential; electrical charges, in this case carried by ions, passively flow
between the active and adjacent resting regions on both the inside and outside of the membrane. Any
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flow of electrical charges is called a current. By convention, the direction of current flow is always
designated by the direction in which the positive charges are moving (i.e. inside the cell and not
outside the cell as seen in Figure C).
In this manner, current spreads in both directions away from the initial site of the potential change.
(a) The membrane of an excitable cell at resting potential
(b) A triggering event opens Na channels, leading to the Na entry that brings about depolarization. The adjacent inactive areas are still at resting potential
(c) Local current flow occurs between the active and adjacent inactive areas. This local current
flow results in depolarization of the previously inactive areas. In this way, the depolarization
spreads away from its point of origin
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The amount of current that flows between two areas depends
1. The difference in potential between the areas. The greater the difference in potential, the greater the
current flow.
2. The strength of stimuli
3. Local potential: Local potential produced in response to several stimuli is larger than one produced
from a single stimuli.
4. The resistance of the material through which the charges are moving. The lower the resistance,
the greater the current flow.
The current does not flow across the plasma membrane's lipid bi-layer.
The current, carried by ions, can move across the membrane only through ion channels.
Graded potentials die out over short distance (decrement fashion):

Current is lost across the plasma membrane as charge-carrying ions leak through the "uninsulated" parts of the membrane, that is, through open channels. Because of this current loss, the
magnitude of the local current progressively diminishes with increasing distance from the initial site of
origin. Thus the magnitude of the graded potential continues to decrease the farther it moves away
from the initial active area. Another way of saying this is that the spread of a graded potential is
decrement (gradually decreases)

Although graded potentials have limited signaling distance, they are critically important to the
body's function. The following are all graded potentials: postsynaptic potentials, receptor potentials, endplate potentials, pacemaker potentials, and slow-wave potentials.
Resting membrane potential:
When two electrodes are connected through a suitable amplifier to a Cathode ray oscilloscope and
placed on the surface of single axon, no potential difference is observed. However, if one electrode is
inserted into the interior of the cell, a constant potential difference is observed, with the inside negative
relative to outside of the cell at rest. The resting membrane potential is found in almost all cells. In
neurons, it is usually about -70 mV.
Resting (Cell at rest), membrane (on two side of the cell membrane), potential (voltage difference)
-70 mV (inside the cell is less than outside the cell by 70 mV)
The transfer of an incredibly small number of ions through the membrane can establish the normal
“resting potential” of −90 millivolts inside the nerve fiber, which means that only about 1/3,000,000 to
1/100,000,000 of the total positive charges inside the fiber must be transferred. Also, an equally small
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number of positive ions moving from outside to inside the fiber can reverse the potential from −90
millivolts to as much as +35 millivolts within as little as 1/10,000 of a second. Rapid shifting of ions in
this manner causes the nerve signals.
Action potential:
Action potential event
The first manifestation of the approaching action potential is a beginning depolarization of the
membrane. After an initial 15 mV of depolarization, the rate of depolarization increases. The point at
which this change in rate occurs is called the firing level or the threshold (-55mV). Therefore, the
tracing on the oscilloscope rapidly reaches and overshoots the iso-potential (zero potential) line to
an approximately +35mV.
It is then reverses and falls rapidly toward the resting level. When re-polarization is about 70%
completed, the rate of re-polarization decreases and the tracing approaches the resting level more
slowly. The sharp rises and rapidly fall are the spike potential of the axon, and the slower fall at the
end of the process is the after-depolarization (about 4ms). After reaching the previous resting level,
the tracing overshoots slightly in hyper-polarization direction to form the small but prolonged afterhyper-polarization (the period that persists until the membrane potassium permeability returns to its
usual value). When recorded with one electrode in the cell, the action potential is called mono-phasic,
because it is primarily in one direction. After-hyper-polarization is about 1 to 2 mV in amplitude and
lasts about 40 ms
10
a. De-polarization (or upstroke) makes the membrane potential less negative (the cell interior
becomes less negative).
b. Re-polarization (or down stroke) the return of cell membrane potential to resting potential after
depolarization.
c. Hyper-polarization (or under stroke) makes the membrane potential more negative (the cell interior
becomes more negative).
d. Inward current is the flow of positive charge into the cell. Inward current depolarizes the membrane
potential.
e. Outward current is the flow of positive charge out of the cell. Outward current hyper-polarizes the
membrane potential.
f. Action potential is a property of excitable cells (i.e., nerve, muscle) that consists of a rapid
depolarization, or upstroke, followed by re-polarization of the membrane potential.
3. Ionic basis of action potential:
a. Resting membrane potential
• is approximately -70 mV, cell negative.
• is the result of the high resting conductance to K+, which drives the membrane potential toward the
K+ equilibrium potential.
• At rest, the Na+ channels are closed and Na+ conductance is low.
b. Upstroke (or depolarization) of the action potential
(1) Inward current depolarizes the membrane potential to threshold.
A negative current value (i.e., inward current) can reflect either the movement of positive ions (cations)
into the cell or negative ions (anions) out of the cell. ‫مما يتسبب ان يصبح داخل الخلية موجب اكثر‬
(2) Depolarization causes rapid opening of the activation gates of the Na+ channel, and the Na+
conductance of the membrane promptly increases.
(3) The Na+ conductance becomes higher than the K+ conductance, and the membrane potential is
driven toward (but does not quite reach) the Na+ equilibrium potential of +65 mV. Thus, the rapid
depolarization during the upstroke is caused by an inward Na+ current.
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(4) The overshoot is the brief portion at the peak of the action potential when the membrane potential
is positive.
c. Down-stroke (or Re-polarization) of the action potential
(1) Depolarization also closes the inactivation gates of the Na+ channel (but more slowly than it opens
the activation gates). Closure of the inactivation gates results in closure of the Na+ channels, and the
Na+ conductance returns toward zero.
(2) Depolarization slowly opens K+ channels and increases K+ conductance to even higher levels
than at rest.
(3) The combined effect of closing the Na+ channels and greater opening of the K+ channels makes
the K+ conductance higher than the Na+ conductance, and the membrane potential is re-polarized.
Thus, re-polarization is caused by an outward K+ current.
d. Undershoot (hyperpolarizing after potential)
• The K+ conductance remains higher than at rest for some time after closure of the Na+ channels.
During this period, the membrane potential is driven very close to the K+ equilibrium potential.
d. Undershoot (hyperpolarizing after potential)
• The K+ conductance remains higher than at rest for some time after closure of the Na+ channels.
During this period, the membrane potential is driven very close to the K+ equilibrium potential
Activation and Inactivation of the Voltage Gated Sodium Channel
The voltage-gated sodium channel in three separate states
A. Resting membrane potential (at -70mV):
Closed but capable of opening
Activation gate is closed
Inactivation gate is opened
No Na passes
B. Depolarization (from – 50mV to+35mV)
Open, or activated
Activation gate is opened
Inactivation gate is opened
Na passes
C. Repolarization (from +30mV to-70mV)
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Closed and not capable of opening
Activation gate is opened
Inactivation gate is closed
No Na passes
The sodium channel inactivation process is that the inactivation gate will not reopen until the
membrane potential returns to or near the original resting membrane potential level. Therefore, it is
usually not possible for the sodium channels to open again without first repolarization the nerve fiber.
Voltage Gated Potassium Channel and Its Activation
During the resting state (left) and toward the end of the action potential (right)
During the resting state, the gate of the potassium channel is closed and potassium ions are prevented
from passing through this channel to the exterior. When the membrane potential rises from −70
millivolts toward zero, this voltage change causes a conformational opening of the gate and allows
increased potassium diffusion outward through the channel. However, because of the slight delay in
opening of the potassium channels, for the most part, they open just at the same time that the sodium
13
channels are beginning to close because of inactivation. Thus, the decrease in sodium entry to the
cell and the simultaneous increase in potassium exit from the cell combine to speed the repolarization
process, leading to full recovery of the resting membrane potential within another few 10,000ths of a
second.
Features of graded potentials and action potentials
Graded potentials
Action potentials
Depending on the stimulus, graded potentials
Action potentials always lead to depolarization
can be depolarizing or hyperpolarizing.
of membrane and reversal of the membrane
potential.
Amplitude is proportional to the strength of the Amplitude is all-or-none; strength of the
stimulus.
stimulus is coded in the frequency of all-ornone action potentials generated.
Amplitude is generally small (a few mV to tens Large amplitude of ~100 mV.
of mV).
Duration of graded potentials may be a few
Action potential duration is relatively short; 3-5
milliseconds to seconds.
ms.
Ion channels responsible for graded potentials Voltage-gated Na+ and voltage-gated K+
may be ligand-gated (extracellular ligands
channels are responsible for the neuronal
such as neurotransmitters), mechanoaction potential.
sensitive, or temperature sensitive channels, or
may be channels that are gated by
cytoplasmic signaling molecules.
The ions involved are usually Na+, K+, or Cl−.
The ions involved are Na+ and K+ (for neuronal
action potentials).
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No refractory period is associated with graded
potentials.
Graded potentials can be summed over time
(temporal summation) and across space
(spatial summation).
Graded potentials travel by passive spread
(electrotonic spread) to neighboring membrane
regions.
Absolute and relative refractory periods are
important aspects of action potentials.
Summation is not possible with action
potentials (due to the all-or-none nature, and
the presence of refractory periods).
Action potential propagation to neighboring
membrane regions is characterized by
regeneration of a new action potential at every
point along the way.
Amplitude diminishes as graded potentials
Amplitude does not diminish as action
travel away from the initial site (decremental).
potentials propagate along neuronal projections
(non-decremental).
Graded potentials are brought about by external Action potentials are triggered by membrane
stimuli (in sensory neurons) or by
depolarization to threshold. Graded potentials
neurotransmitters released in synapses, where are responsible for the initial membrane
they cause graded potentials in the postdepolarization to threshold.
synaptic cell.
Re-establishing Sodium and Potassium ionic grading after action potentials are completed
(importance of energy metabolism)
1. For a single action potential, the energy expenditure for Na+-K+ pump is so minute that it cannot
be measured. Indeed, 100,000 to 50 million impulses can be transmitted by large nerve fibers before
the concentration differences reach the point that action potential conduction ceases.
2. A special feature of the Na+-K+ATPase pump is that its degree of activity is strongly stimulated
when excess sodium ions accumulate inside the cell membrane. In fact, the pumping activity increases
approximately in proportion to the third power of this intracellular sodium concentration. That is, as the
internal sodium concentration rises from 10 to 20 mEq/L, the activity of the pump does not merely
double but increases about eightfold. Therefore, it is easy to understand how the “recharging” process
of the nerve fiber can be set rapidly into motion whenever the concentration differences of sodium and
potassium ions across the membrane begin to “run down.”
3. The nerve fiber produces excess heat during recharging, which is a measure of energy expenditure
when the nerve impulse frequency increases.
General characteristics of nerve:
1. ALL-or-none Law:
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Threshold potential (Threshold intensity): It is the minimal intensity of stimulating current that, acting
for a given duration, will just produce an action potential is the membrane potential at which the action
potential is inevitable‫ال مفر منه‬. At threshold potential, net inward current becomes larger than net
outward current.
Electronic potentials: Although sub-threshold stimuli do not produce an action potential, they do have
an effect on the membrane potential.
If net inward current is less than net outward current, no action potential will occur (i.e., all-or-none
response
All-or-none law: The all-or-none law is the principle that the strength by which a nerve or muscle
fiber responds to a stimulus is independent of the strength of the stimulus. If that stimulus exceeds
the threshold potential, the nerve or muscle fiber will give a complete response; otherwise, there is no
response.
Further increase in the intensity of a stimulus (Supra-threshold stimulus) produces no increment or
other change in the action potential as long as the other experimental condition remains constant. The
action potential fails to occur if the stimulus is sub-threshold in magnitude, and it occurs with constant
amplitude and form regardless of the strength of the stimulus if the stimulus is at or above the threshold
intensity.
The above account deals with the response of a single nerve fiber. If a nerve trunk is stimulated, then
as the exciting stimulus is progressively increased above threshold, a larger number of fibers respond.
The minimal effective (i.e., threshold) stimulus is adequate only for fibers of high excitability, but a
16
stronger stimulus excites all the nerve fibers. Increasing the stimulus further does increase the
response of whole nerve
2. Propagation of action potentials

The conduction is an active, self-propagating process, and the impulse moves along
the nerve at a constant amplitude and velocity.

The electrical events in neurons are rapid, being measured in milli-seconds (ms), and the
potential changes are small, being measured in milli-volts (mV).
Propagation occurs by the spread of local currents to adjacent areas of membrane, which are then
depolarized to threshold and generate action potentials.
Conduction velocity is increased by:
a. increase fiber size. Increasing the diameter of a nerve fiber results in decreased internal resistance;
thus, conduction velocity down the nerve is faster.
b. Myelination.
Myelin acts as an insulator around nerve axons and increases conduction velocity.
Depolarization in myelinated axons jumps from one node of Ranvier to the next this is called (saltatory
conduction).
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Because the cytoplasm of the axon is electrically conductive and because the myelin inhibits charge
leakage through the membrane depolarization at one node of Ranvier is sufficient to elevate the
voltage at a neighboring node to the threshold for action potential initiation. Thus in myelinated axons,
action potentials do not propagate as waves, but recur ‫تكرر‬at successive nodes and in effect "hop"
‫قفز‬along the axon, by which process they travel faster up to 50 times faster than the fast un-myelinated
fibers. Action potential in unmylinated axon occurs over the entire of the axon membrane
The spatial distribution of ion channels along the axon plays a key role in the initiation and regulation
of the action potential. Voltage-gated Na+ channels are highly concentrated in the nodes of Ranvier
and the initial segment in myelinated neurons.
The number of Na channel per square micro-meter of membrane in myelinated mammalian neurons
has been estimated to be

2000-12,000 at the nodes of Ranvier.

Along the axon of un-myelinated neurons, the number is about 110
In many myelinated number neurons, the Na channels are flanked ‫يحيط‬by K channels that are involved
in re-polarization.
In summary, the charge will passively depolarize the adjacent node of Ranvier to threshold,
triggering an action potential in this region and subsequently depolarizing the next node, and so on.
3. Stereotypical size and shape
Each normal action potential for a given cell type look identical, depolarizes to the same potential, and
repolarizes back to the same resting potential
4. Refractory periods
a. Absolute refractory period
• is the period during which another action potential cannot be elicited, no matter how large the
stimulus.
• coincides ‫يتزامن‬with almost the entire duration of the action potential.
• Explanation: Recall ‫تذكر‬that the inactivation gates of the Na+ channel are closed when the
membrane potential is depolarized. They remain closed until re-polarization occurs. No action
potential can occur until the inactivation gates open.
b. Relative refractory period
• begins at the end of the absolute refractory period and continues until the membrane potential
returns to the resting level.
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• An action potential can be elicited during this period only if a larger than usual inward current is
provided.
• Explanation: The K+ conductance is higher than at rest, and the membrane potential is closer to the
K+ equilibrium potential and, therefore, farther from threshold; more inward current is required to bring
the membrane to threshold.
Ortho-dromic and anti-dromic conduction: An axon can conduct in either direction. When an action
potential is initiated in the middle of it, two impulses traveling in opposite directions are set up by
electro-tonic depolarization on either side of the initial current sink.
In a living animal, impulses normally pass in one direction only, i.e. from synaptic junction or receptors
along axons to their termination. Such conduction is called” ortho-dromic “. Conduction in the opposite
direction is called “anti-dromic”. Since synapses, unlike axons, permit conduction in one direction only,
any anti-dromic impulses that are set up fail to pass the first synapses they encounter and die out at
that point
Nerve accommodation
The ability of nerve tissue to adjust to a constant source and intensity of stimulation so that some
change in either intensity or duration of the stimulus is necessary to elicit a response beyond the initial
reaction
Potassium is the most abundant intracellular cation and about 98% of the body's potassium is found
inside cells, with the remainder in the extracellular fluid including the blood.
Increased extracellular potassium levels result in depolarization of the membrane potentials of cells
due to the increase in the equilibrium potential of potassium. This depolarization opens some voltagegated sodium channels, but also increases the inactivation at the same time. Since depolarization due
to concentration change is slow, it never generates an action potential by itself; instead, it results
19
in accommodation. Above a certain level of potassium the depolarization inactivates sodium channels,
opens potassium channels, thus the cells become refractory.
Hyperkalemia open gates of K membrane potential is closer to threshold (Nernst equation)
inactivation gates on Na accommodation muscle weakness
Synaptic Transmission:
Functional anatomy:
As many as 10,000 to 200,000 minute synaptic knobs called presynaptic terminals lie on the surfaces
of the dendrites and soma of the motor neuron, with about 80 to 95 percent of them on the dendrites
and only 5 to 20 percent on the soma
The ends of the pre-synaptic fibers are generally enlarged to form (terminal buttons or synaptic knob)
and it will synapse with:
I.Axo-dendritic: In the cerebral and cerebellar cortex, ending are commonly located, on dendrites and
frequently on (dendritic spines: which are small knobs projecting from dendrites).
II. Axo-somatic: The terminal branches of the axon of the pre-synaptic neuron form a basket or net
around the soma of post-synaptic cell (“basket cells” of the cerebellum and autonomic ganglia).
III. Axo-axonal: they terminate on the axon of the post-synaptic cell.
Types of synapses:
1. Electrical synaptic transmission:
 In a few locations (e.g., within the retina and olfactory bulb), synaptic transmission is
accomplished by the passive electronic spread of current between two cells.
 Specialized junctions called (gap junctions) allow the spread of current between two cells. Only
2-4nm separates the pre and post-synaptic membranes at the site of gap junctions (and the distance
between the cells).
20
 Gap junctions are formed by (membrane brides) that are constructed from integral membrane
proteins called (connexin).
 An aqueous channel is formed in the membrane by six molecules of connexin.
 The channel in one cell merges with a channel in the membrane of another cell to form the gap
junction, enabling small molecules and ions to pass from one cell to the other, thus establishing
cytoplasmic continuity.
 When an action potential propagating along the membrane in one cell reaches the gap junction,
an electrical current flows passively through the gap from one cell to another.
 Electrical current can pass through the gap in both directions, allowing either cell to serve as
the pre- and post-synaptic cell.
2. Chemical synaptic transmission:
Introduction:
There is always more than one neuron involved in the transmission of a nerve impulse from its origin
to its destination, whether it is sensory or motor.
There is no physical contact between these neurons.
The point at which the nerve impulse passes from one to another is the synapse.
There are the junctions where the axon or some other portion of one cell (the pre-synaptic cell)
terminates on the dendrites, soma, or axon of another neuron, or in some cases a muscle or gland
cell (the post-synaptic cell). The transmission at most synaptic junction is chemical; the impulse in the
pre-synaptic axon causes secretion of a (neuro-transmitter) such as acetylcholine.
21
Electron microscopic studies of the presynaptic terminals show that they have varied anatomical
forms, but most of them resemble small round or oval knobs and, therefore, are sometimes called
terminal knobs, boutons, end-feet, or synaptic knobs
.
At its free end, the axon of the pre-synaptic neuron breaks up into minute branches that terminate in
small swellings called synaptic knobs, or terminal buttons. The vesicle and the proteins contained in
their walls are synthesized in the Golgi apparatus in the neuronal cell body and migrate down the axon
to the ending by fast axo-plasmic transport.
Role of synapses in processing information:
1. Synapses determine the directions that the nervous signals will spread through the nervous system.
Some
2. Facilitate or inhibit signals
3. Postsynaptic neurons respond with large numbers of output impulses, and others respond with only
a few numbers of output impulses
4. Synapses perform a selective action, often blocking weak signals while allowing strong signals to
pass, but at other times selecting
5. Synapses perform amplifying certain weak signals and often channeling these signals in many
directions rather than in only one direction
General events at pre-synaptic end:
1. An action potential in the pre-synaptic cell causes depolarization of the pre-synaptic terminal.
2. As a result of the depolarization, Ca2+ enters the pre-synaptic terminal by N-type calcium channels
(voltage-gated calcium channels),
3. The vesicles are loaded with transmitter in the ending, fuse with the membrane, and causing release
of neurotransmitter into the synaptic cleft by exo-cytosis, and then are retrieved by endo-cytosis. They
enter endosomes and are budded off the endosomes and refilled, starting the cycle over again.
For the vesicles that store the neurotransmitter acetylcholine, between 2000 and 10,000 molecules of
acetylcholine are present in each vesicle, and there are enough vesicles in the presynaptic terminal
to transmit from a few hundred to more than 10,000 action potentials.
Calcium is the key to synaptic vesicle fusion and discharge. An action potential reaching the presynaptic terminal opens voltage-gated calcium channels and the resulting calcium influx triggers
22
release. The calcium content is then restored to the resting level by rapid sequestration and removal
from the cell, primarily by a Ca-Na anti-port.
4. Neurotransmitter diffuses across the synaptic cleft and combines with receptors on the postsynaptic
cell membrane
General events at post-synaptic end:
 Across the synaptic cleft, there are many neurotransmitter receptors in the post-synaptic
thickening called the (post-synaptic density).
 The molecules of these receptors have two important components:
1. Binding component that protrudes outward from the membrane into the synaptic cleft (here it
binds with the neurotransmitter from the pre-synaptic terminal).
2. Intracellular component that passes all the way through the postsynaptic membrane to the
interior of the postsynaptic neuron.
Receptor activation controls the opening of ion channels in the postsynaptic cell in one of two ways:
(a) by gating ion channels directly and allowing passage of specified types of ions through the
membrane
23
The ionophore in turn is one of two types:
Carrier ionophores that bind to a particular ion and shield its charge from the surrounding
environment
Channel ionophores introduce a hydrophilic pore into the membrane, allowing ions to pass through
without coming into contact with the membrane's hydrophobic interior
(b) by activating a “second messenger”
Neurotransmitter receptors that directly gate ion channels are often called ionotropic receptors,
whereas those that act through second messenger systems are called metabotropic receptors.
Activating a “second messenger” is suitable for causing prolonged postsynaptic neuronal changes (for
instance, the process of memory); while activating a “ionic channels” is suitable for causing short term
postsynaptic neuronal changes
 One way conduction: Synapses generally permit conduction of impulses in one direction only,
from the pre- to post-synaptic neurons. Chemical mediation at synaptic junction explains one-way
conduction. A one-way conduction mechanism allows signals to be directed toward specific goals.
Neural circuit:
Convergence: many pre-synaptic neurons converge on any single post-synaptic neurons.
Divergence: the axon of most pre-synaptic neurons divided into branches that diverge to end on many
post-synaptic neurons.
Chemical transmission of the synaptic activity:
Receptors:
The general characteristics of the receptors are:
24
First: For each ligand there are many sub-types of receptors, for example, nor-epinephrine act on
alpha1 and alpha2.
Second: there are receptors on the pre-synaptic as well as the post-synaptic elements for many
secreted transmitter. These (pre-synaptic receptors or auto-receptors) often inhibit further secretion
of the ligand, providing feedback control.
Third: although there are many ligands and many sub-types of receptors for each ligand, the receptors
tend to group in large families as far as structure and function are concerned.
Fourth: receptors are concentrated in cluster in post-synaptic structure close to the ending of neurons
that secrete the neurotransmitter specific for them. This is generally due to the presence of specific
binding proteins for them.
Fifth: prolonged exposure to their ligands causes most receptors to become unresponsive, i.e., to
undergo down regulation or de-sensitization. This can be of two types:
1.
Homo-logous de-sensitization: with loss of responsiveness only to the particular ligand and
maintain responsiveness of the cell to other ligands.
2.
Hetero-logous de-sensitization: in which the cell become un-responsiveness to other ligands
as well.
Desensitization also referred as adaptation, refractoriness, down-regulation while tolerance is
describe more gradual decrease in response to ligand which may takes days or weeks to develop
Reuptake or re-uptake:
It is the reabsorption of a neurotransmitter by a neurotransmitter transporter of pre-synaptic neurons
after it has performed its function of transmitting a neuronal impulse.
Reuptake is necessary for normal synaptic physiology because it allows for the recycling of
neurotransmitter and regulates the level of neurotransmitter present in the synapse, thereby
controlling how long a signal resulting from neurotransmitter release lasts.
Because neurotransmitters are too large and hydrophilic to diffuse through the membrane, specific
transport proteins are necessary for the reabsorption of neurotransmitters.
Neurotransmitters
Small-Molecule, Rapidly Acting Transmitters
Class I: Acetylcholine
Class II (The Amines): Norepinephrine, Epinephrine, Dopamine, Serotonin, Histamine
Class III (Amino Acids): Gamma-aminobutyric acid, Glycine, Glutamate, Aspartate
Class IV: Nitric oxide
Class I:
Acetylcholine (Ach):
 Acetylcholine is found in neurons release acetylcholine (cholinergic neurons).
 Synthesis of acetylcholine involves the reaction of choline with acetate.
 Choline is an important amine that is also precursor of  membrane phospholipids
phosphatidyl-choline and  sphingo-myline and the signaling phospholipids platelet-activating
factor.
 Choline is also synthesized in neurons.
 The acetate is activated by the combination of acetate groups with reduced coenzyme A.
25
 The reaction between active acetate (acetyl-coenzyme A, acetyl-CoA) and choline is catalyzed
by enzyme (choline acetyl-transferase). Acetylcholine is stored in synaptic vesicles with ATP and
proteoglycan for later release.
 Acetylcholine is then taken up into synaptic vesicle by a vesicular transporter (VAChT:
vesicular acetylcholine transporter).
Destruction of the Released Acetylcholine by Acetylcholinesterase
The acetylcholine, once released into the synaptic space, continues to activate the acetylcholine
receptors as long as the acetylcholine persists in the space. However, it is removed rapidly by two
means:
(1) Most of the acetylcholine is destroyed by the enzyme acetylcholinesterase, which is attached
mainly to the spongy layer of fine connective tissue that fills the synaptic space between the
presynaptic nerve terminal and the post synaptic muscle membrane, and
(2) a small amount of acetylcholine diffuses out of the synaptic space and is then no longer available
to act on the muscle fiber membrane.
One-half of the choline is taken back into the pre-synaptic ending by Na+–choline co-transport and
used to synthesize new of Acetylcholine.
Class II: The Amines
1. Nor-epinephrine, epinephrine, and dopamine
(1) Nor-epinephrine:
26
• is the primary transmitter released from postganglionic sympathetic neurons.
• is synthesized in the nerve terminal and released into the synapse to bind with ά or β receptors on
the postsynaptic membrane.
Specifically, nor-epinephrine secreting neurons located in the locus ceruleus in the pons send nerve
fibers to widespread areas of the brain to help control overall activity and mood of the mind, such as
increasing the level of wakefulness. In most of these areas, norepinephrine probably activates
excitatory receptors, but in a few areas, it activates inhibitory receptors instead
• is removed from the synapse by reuptake or is metabolized in the pre-synaptic terminal by
monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).
(2) Epinephrine
• is synthesized from nor-epinephrine
• is secreted, along with nor-epinephrine, from the adrenal medulla.
(3) Dopamine
There are 5 different types of dopamine receptors (D1, D2, D3, D4, and D5)
Dopamine is prominent in midbrain neurons.
Dopamine is released from the hypothalamus and inhibits prolactin secretion; in this context it is called
prolactin-inhibiting factor (PIF).
Dopamine is secreted by neurons that originate in the substantia nigra.The termination of these
neurons is mainly in the striatal region of the basal ganglia.The effect of dopamine is usually inhibition.
• is metabolized by MAO and COMT
2. Serotonin (5-Hydroxy-tryptamine: 5-HT)
There are different types of 5-HT receptors: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2C, 5-HT3 and 5HT4)
Serotonin is formed from tryptophan and converted to melatonin in the pineal gland.
Serotonin is present in highest concentration in blood platelets and in the GIT, lesser amount is
found in the brain and retina
Serotonins receptors (HT) have been found as:
5-HT2A receptors mediate platelet aggregation and smooth muscle contraction
 5-HT4 receptors are present in GIT, where they facilitate secretion and peristalsis
5-HT6 and 5- HT7 receptors in the brain are distributed throughout the limbic system.
Serotonin is secreted by nuclei that originate in the median raphe of the brain stem and project to
many brain and spinal cord areas, especially to the dorsal horns of the spinal cord and to the
hypothalamus.
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Serotonin acts as an inhibitor of pain pathways in the cord, and an inhibitor action in the higher regions
of the nervous system is believed to help control the mood of the person, perhaps even to cause sleep
3. Histamine
There are two receptors (H1, H2)
• is formed from histidine.
• is present in the neurons of the hypothalamus.
Class III: Amino Acids
1. Glutamate
• is the most prevalent excitatory neurotransmitter in the brain.
2. GABA (Gama amino-buteric acid)
• is an inhibitory neurotransmitter.
• is synthesized from glutamate by glutamate de-carboxylase.
• It has two types of receptors:
(1) The GABAA receptor increases CI- conductance.
(2) The GABAB receptor increases K+ conductance.
3. Glycine
• is an inhibitory neurotransmitter found primarily in the spinal cord and brain stem.
• Increases CI- conductance
Class IV
Nitric oxide (NO)
Nitric oxide is a short-acting inhibitory neurotransmitter in the gastrointestinal tract, blood vessels, and
the central nervous system.
Nitric oxide is especially secreted by nerve terminals in areas of the brain responsible for long-term
behavior and for memory. Therefore, this transmitter system might in the future explain some behavior
and memory functions that thus far have defied understanding.
Nitric oxide is different from other small molecule transmitters in its mechanism of formation in the
presynaptic terminal and in its actions on the postsynaptic neuron.
Nitric oxide is not preformed and stored in vesicles in the presynaptic terminal as are other
transmitters. Nitric oxide is synthesized almost instantly as needed,

Nitric oxide then diffuses out of the presynaptic terminals over a period of seconds rather than being
released in vesicular packets

Nitric oxide diffuses into postsynaptic neurons nearby.

Nitric oxide in the postsynaptic neuron, it usually does not greatly alter the membrane potential but
instead changes intracellular metabolic functions that modify neuronal excitability for seconds,
minutes, or perhaps even longer.
Input to synapses
Uniform distribution of electrical potential inside the soma
The interior of the neuronal soma contains a highly conductive electrolytic solution, the intracellular
fluid of the neuron. Furthermore, the diameter of the neuronal soma is large (from 10 to 80
micrometers), causing almost no resistance to conduction of electric current from one part of the somal
28
interior to another part. Therefore, any change in potential in any part of the intra-somal fluid causes
an almost exactly equal change in potential at all other points inside the soma (that is, as long as the
neuron is not transmitting an action potential). This is an important principle, because it plays a major
role in “summation” of signals entering the neuron from multiple sources
• The postsynaptic cell integrates excitatory and inhibitory inputs.
• When the sum of the input brings the membrane potential of the postsynaptic cell to threshold, it
fires an action potential.
a. Effect of Synaptic Excitation on the Postsynaptic Membrane (Excitatory postsynaptic potentials
(EPSPs)):
Excitatory neurotransmitters include ACh, nor epinephrine, epinephrine, dopamine, glutamate, and
serotonin.
A. The resting membrane potential everywhere in the soma is -65 millivolts.
B. a presynaptic terminal that has secreted an excitatory transmitter into the cleft between the terminal
and the neuronal somal membrane
1. Neurotransmitter acts on the membrane excitatory receptor to increase the membrane’s
permeability to Na+. Because of the large sodium concentration gradient and large electrical negativity
inside the neuron, sodium ions diffuse rapidly to the inside of the membrane.
2. The rapid influx of positively charged sodium ions to the interior neutralizes part of the negativity of
the resting membrane potential. Thus, the resting membrane potential has increased in the positive
direction from -65 to -45 millivolts.
This positive increase in voltage above the normal resting neuronal potential—that is, to a less
negative value—is called the excitatory postsynaptic potential (or EPSP), because if this potential
rises high enough in the positive direction, it will elicit an action potential in the postsynaptic neuron,
29
thus exciting it. (In this case, the EPSP is +20 millivolts—that is, 20 millivolts more positive than the
resting value.) However, we must issue a word of warning.
Discharge of a single presynaptic terminal can never increase the neuronal potential from -65 millivolts
all the way up to -45 millivolts. An increase of this magnitude requires process called summation
3. Generation of action potentials in the initial segment of the axon leaving the neuron (Threshold for
Excitation)
When the EPSP rises high enough in the positive direction (reaching the threshold for excitation),
there comes a point at which this initiates an action potential in the neuron. However, the action
potential does not begin adjacent to the excitatory synapses. Instead, it begins in the initial segment
of the axon where the axon leaves the neuronal soma. The main reason for this point of origin of the
action potential is that the soma has relatively few voltage-gated sodium channels in its membrane,
which makes it difficult for the EPSP to open the required number of sodium channels to elicit an
action potential. Conversely, the membrane of the initial segment has seven times as great a
concentration of voltage-gated sodium channels as does the soma and, therefore, can generate an
action potential with much greater ease than can the soma.
The EPSP that will elicit an action potential in the axon initial segment is between +10 and +20
millivolts. This is in contrast to the +30 or +40 millivolts or more required on the soma. Once the action
potential begins, it travels peripherally along the axon and usually also backward over the soma. In
some instances, it travels backward into the dendrites, too, but not into all of them, because they, like
the neuronal soma, have very few voltage gated sodium channels and therefore frequently cannot
generate action potentials at all.
Thus, the threshold for excitation of the neuron is shown to be about -45 millivolts, which represents
an EPSP of +20 millivolts—that is, 20 millivolts more positive than the normal resting neuronal
potential of -65 millivolts.
Possible mechanisms of EPSP
1. Opening of sodium channels to allow large numbers of positive electrical charges to flow to the
interior of the postsynaptic cell. This action raises the intracellular membrane potential in the positive
direction up toward the threshold level for excitation. It is by far the most widely used means for
causing excitation.
2. Depressed conduction through chloride or potassium channels, or both. This action decreases the
diffusion of negatively charged chloride ions to the inside of the postsynaptic neuron or decreases the
30
diffusion of positively charged potassium ions to the outside. In either instance, the effect is to make
the internal membrane potential more positive than normal, which is excitatory.
3. Various changes in the internal metabolism of the postsynaptic neuron to excite cell activity or, in
some instances, to increase the number of excitatory membrane receptors or decrease the number
of inhibitory membrane receptors.
b. Effect of Inhibitory Synapses on the Postsynaptic Membrane (Inhibitory postsynaptic potentials
(IPSPs)):
Inhibitory neurotransmitters are γ-amino-butyric acid (GABA) and glycine.
The inhibitory synapses open mainly chloride channels, allowing easy passage of chloride ions.
A. Effect of opening of Chloride Channels:
31
Calculated Nernst potential for chloride ions to be about -70 millivolts: this potential is more negative
than the -65 millivolts normally present inside the resting neuronal membrane. Therefore, opening the
chloride channels will allow negatively charged chloride ions to move from the extracellular fluid to the
interior, which will make the interior membrane potential more negative than normal, approaching the
-70 millivolt level.
B. Effect of opening of Potassium Channels:
Opening potassium channels will allow positively charged potassium ions to move to the exterior, and
this will also make the interior membrane potential more negative than usual.
Thus, both chloride influx and potassium efflux increase the degree of intracellular negativity, which
is called hyperpolarization. This inhibits the neuron because the membrane potential is even more
negative than the normal intracellular potential. Therefore, an increase in negativity beyond the normal
resting membrane potential level is called an inhibitory postsynaptic potential (IPSP).
The effect on the membrane potential caused by activation of inhibitory synapses, allowing chloride
influx into the cell and/or potassium efflux out of the cell, with the membrane potential decreasing from
its normal value of -65 millivolts to the more negative value of -70 millivolts: This membrane potential
is 5 millivolts more negative than normal and is therefore an IPSP of -5 millivolts, which inhibits
transmission of the nerve signal through the synapse.
Possible mechanisms of IPSP
1. Opening of chloride ion channels through the postsynaptic neuronal membrane.
This action allows rapid diffusion of negatively charged chloride ions from outside the postsynaptic
neuron to the inside, thereby carrying negative charges inward and increasing the negativity inside,
which is inhibitory.
2. Increase in conductance of potassium ions out of the neuron. This action allows positive ions to
diffuse to the exterior, which causes increased negativity inside the neuron; this is inhibitory.
3. Activation of receptor enzymes that inhibit cellular metabolic functions that increase the number of
inhibitory synaptic receptors or decrease the number of excitatory receptors.
Time Course of Postsynaptic Potentials
When an excitatory postsynaptic potential (EPSP) excited, the neuronal membrane becomes highly
permeable to sodium ions for 1 to 2 milliseconds.
During this very short time, enough sodium ions diffuse rapidly to the interior of the postsynaptic motor
neuron to increase its intra-neuronal potential by a few millivolts, thus creating the excitatory
postsynaptic potential (EPSP)
32
This potential then slowly declines over the next 15 milliseconds because this is the time required for
the excess positive charges to leak out of the excited neuron and to re-establish the normal resting
membrane potential.
Precisely the opposite effect occurs for an IPSP; that is, the inhibitory synapse increases the
permeability of the membrane to potassium or chloride ions, or both, for 1 to 2 milliseconds, and this
decreases the intra-neuronal potential to a more negative value than normal, thereby creating the
IPSP. This potential also dies away in about 15 milliseconds.
Other types of transmitter substances can excite or inhibit the postsynaptic neuron for much longer
periods—for hundreds of milliseconds or even for seconds, minutes, or hours. This is especially true
for some of the neuropeptide types of transmitter substances.
Summation at synapses
Many presynaptic terminals are usually stimulated at the same time. Even though these terminals are
spread over wide areas of the neuron, their effects can still summate; that is, they can add to one
another until neuronal excitation does occur
a. Spatial summation occurs when two excitatory inputs arrive at a postsynaptic neuron
simultaneously‫آن واحد‬
ٍ ‫ في‬.
In spatial summation multiple postsynaptic potentials from different synapses occur about the same
time and sum. Together, they produce greater depolarization.
b. Temporal summation occurs when two excitatory inputs arrive at a postsynaptic neuron in rapid
succession ‫توال سريع‬.
In temporal summation postsynaptic potentials at the same synapse occur in rapid succession.
Because the resulting postsynaptic de-polarizations overlap in time, they add in stepwise fashion.
1. If a neuron is being excited by an EPSP, an inhibitory signal from another source can often reduce
the postsynaptic potential to less than threshold value for excitation, thus turning off the activity of the
neuron; thus summation can occurs by both EPSP and IPSP at the same time.
33
2. When the cell has excite and membrane potential is nearer the threshold for firing than normal but
is not yet at the firing level (the neuron is said to be facilitated). Consequently, another excitatory
signal entering the neuron from some other source can then excite the neuron very easily.
Special function of dendrites for exciting neurons:
 Between 80 and 95 percent of all the presynaptic terminals of the anterior motor neuron
terminate on dendrites, in contrast to only 5 to 20 percent terminating on the neuronal soma.
 The dendrites often extend 500 to 1000 micrometers in all directions from the neuronal soma,
and these dendrites can receive signals from a large spatial area around the motor neuron
 The conduction of excitation begins from dendrites to soma and then to axon
Most dendrites fail to transmit action potentials because
Their membranes have relatively few voltage gated sodium channels, and their thresholds for
excitation are too high for action potentials to occur.
Yet they do transmit electro-tonic current down the dendrites to the soma.
A large share of the EPSP is lost before it reaches the soma. The reason a large share is lost is
that the dendrites are long, and their membranes are thin and at least partially permeable to
potassium and chloride ions, making them “leaky” to electric current. Therefore, before the
excitatory potentials can reach the soma, a large share of the potential is lost by leakage through
34
the membrane. This decrease in membrane potential as it spreads electro-tonically along dendrites
toward the soma is called decremental conduction
The farther the excitatory synapse is from the soma of the neuron, the greater will be the decrement
and the lesser will be excitatory signal reaching the soma. Therefore, the synapses that lie near
the soma have far more effect in causing neuron excitation or inhibition than do those that lie far
away from the soma.
Some special characteristics of synaptic transmission:
Fatigue of Synaptic Transmission
When excitatory synapses are repetitively stimulated at a rapid rate, the number of discharges by the
postsynaptic neuron is at first very great, but the firing rate becomes progressively less in succeeding
milliseconds or seconds. This phenomenon is called fatigue of synaptic transmission. Fatigue is an
exceedingly important characteristic of synaptic function because when areas of the nervous system
become overexcited, fatigue causes them to lose this excess excitability after a while. For example,
fatigue is probably the most important means by which the excess excitability of the brain during an
epileptic seizure is finally subdued so that the seizure ceases. Thus, the development of fatigue is a
protective mechanism against excess neuronal activity.
The mechanism of fatigue is mainly exhaustion or partial exhaustion of the stores of transmitter
substance in the presynaptic terminals.
The excitatory terminals on many neurons can store enough excitatory transmitter to cause only about
10,000 action potentials, and the transmitter can be exhausted in only a few seconds to a few minutes
of rapid stimulation. Part of the fatigue process probably results from two other factors as well:
(1) progressive inactivation of many of the postsynaptic membrane receptors and
(2) slow development of abnormal concentrations of ions inside the postsynaptic neuronal cell.
Effect of Acidosis or Alkalosis on Synaptic Transmission
Most neurons are highly responsive to changes in pH of the surrounding interstitial fluids.
Normally, alkalosis greatly increases neuronal excitability.
For instance, a rise in arterial blood pH from the 7.4 normal to 7.8 to 8.0 often causes cerebral epileptic
seizures because of increased excitability of some or all of the cerebral neurons.
In a person who is predisposed to epileptic seizures, even a short period of hyperventilation, which
blows off carbon dioxide and elevates the pH, may precipitate an epileptic attack.
Conversely, acidosis greatly depresses neuronal activity; a fall in pH from 7.4 to below 7.0 usually
causes a comatose state.
For instance, in very severe diabetic or uremic acidosis, coma almost always develops.
Effect of Hypoxia on Synaptic Transmission
Neuronal excitability is also highly dependent on an adequate supply of oxygen.
Cessation of oxygen for only a few seconds can cause complete in-excitability of some neurons. This
effect is observed when the brain’s blood flow is temporarily interrupted because within 3 to 7 seconds,
the person becomes unconscious.
Effect of Drugs on Synaptic Transmission
Many drugs are known to increase the excitability of neurons, and others are known to decrease
excitability.
For instance,
35
caffeine, theophylline, and theobromine, which are found in coffee, tea, and cocoa, respectively, all
increase neuronal excitability, presumably by reducing the threshold for excitation of neurons.
Strychnine is one of the best known of all agents that increase excitability of neurons. However, it
does not do this by reducing the threshold for excitation of the neurons; instead, it inhibits the action
of some normally inhibitory transmitter substances, especially the inhibitory effect of glycine in the
spinal cord. Therefore, the effects of the excitatory transmitters become overwhelming, and the
neurons become so excited that they go into rapidly repetitive discharge, resulting in severe tonic
muscle spasms.
Most anesthetics increase the neuronal membrane threshold for excitation and thereby decrease
synaptic transmission at many points in the nervous system. Because many of the anesthetics are
especially lipid soluble, it has been reasoned that some of them might change the physical
characteristics of the neuronal membranes, making them less responsive to excitatory agents.
Synaptic Delay
During transmission of a neuronal signal from a presynaptic neuron to a postsynaptic neuron, a certain
amount of time is consumed in the process of
(1) discharge of the transmitter substance by the presynaptic terminal,
(2) diffusion of the transmitter to the postsynaptic neuronal membrane,
(3) action of the transmitter on the membrane receptor,
(4) action of the receptor to increase the membrane permeability, and
(5) inward diffusion of sodium to raise the EPSP to a high enough level to elicit an action potential.
The minimal period of time required for all these events to take place, even when large numbers of
excitatory synapses are stimulated simultaneously, is about 0.5 milli-second, which is called the
synaptic delay.
Neurophysiologists can measure the minimal delay time between an input volley ‫ وابل‬of impulses into
a pool of neurons and the consequent output volley. From the measure of delay time, one can then
estimate the number of series neurons in the circuit.
Because of it, conduction along a chain of neurons is slower if there are many synapses in the chain
than if there are only a few.
36