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 1-μm constrictions that are about 1 mm apart). Some of neurons are not myelinated (un-myelinated neurons) i.e. are simply surrounded by Schwann cells without the warping of the Schwann cell membrane around the axon that produces myelin.

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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 membraneMembrane 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 CThe 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 chargesMembrane potential is due to difference in the concentration and permeability of key ions

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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 0Intra-cellular 15 150 65Relative 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 potential1. 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 occursThe 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 (E Na+) 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 membraneThe 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 onCi: 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 mVK+ 140 mM 4 mM -85 mVCa+ 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 outSeveral 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 system. The concentration gradient of each of these ions across the membrane helps determine the voltage of the membrane potential.

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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 10-mV 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 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.

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(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 cur-rent flow results in depolarization of the previously inactive areas. In this way, the depolariza-tion spreads away from its point of origin

The amount of current that flows between two areas de pends 1. The difference in potential between the areas. The greater the difference in potential, the greater the current flow.2. The strength of stimuli

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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 "un-insulated" 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, end-plate 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 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.

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Action potential:Action potential eventThe 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 after-hyper-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

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).

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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. الخلية داخل يصبح ان يتسبب مما

اكثر موجب(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.(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

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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 statesA. Resting membrane potential (at -70mV): Closed but capable of openingActivation gate is closed Inactivation gate is openedNo Na passesB. Depolarization (from – 50mV to+35mV) Open, or activatedActivation gate is openedInactivation gate is openedNa passesC. Repolarization (from +30mV to-70mV) Closed and not capable of openingActivation gate is openedInactivation gate is closedNo Na passes

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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 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.

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Features of graded potentials and action potentialsGraded potentials Action potentials

Depending on the stimulus, graded potentials can be depolarizing or hyperpolarizing.

Action potentials always lead to depolarization of membrane and reversal of the membrane potential.

Amplitude is proportional to the strength of the stimulus.

Amplitude is all-or-none; strength of the stimulus is coded in the frequency of all-or-none action potentials generated.

Amplitude is generally small (a few mV to tens of mV).

Large amplitude of ~100 mV.

Duration of graded potentials may be a few milliseconds to seconds.

Action potential duration is relatively short; 3-5 ms.

Ion channels responsible for graded potentials may be ligand-gated (extracellular ligands such as neurotransmitters), mechano-sensitive, or temperature sensitive channels, or may be channels that are gated by cytoplasmic signaling molecules.

Voltage-gated Na+ and voltage-gated K+ channels are responsible for the neuronal action potential.

The ions involved are usually Na+, K+, or Cl−. The ions involved are Na+ and K+ (for neuronal action potentials).

No refractory period is associated with graded potentials.

Absolute and relative refractory periods are important aspects of action potentials.

Graded potentials can be summed over time (temporal summation) and across space (spatial summation).

Summation is not possible with action potentials (due to the all-or-none nature, and the presence of refractory periods).

Graded potentials travel by passive spread Action potential propagation to neighboring 14

(electrotonic spread) to neighboring membrane regions.

membrane regions is characterized by regeneration of a new action potential at every point along the way.

Amplitude diminishes as graded potentials travel away from the initial site (decremental).

Amplitude does not diminish as action potentials propagate along neuronal projections (non-decremental).

Graded potentials are brought about by external stimuli (in sensory neurons) or by neurotransmitters released in synapses, where they cause graded potentials in the post-synaptic cell.

Action potentials are triggered by membrane depolarization to threshold. Graded potentials are responsible for the initial membrane depolarization to threshold.

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: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 inevitable منه مفر At threshold potential, net inward current becomes larger .الthan 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

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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 stronger stimulus excites all the nerve fibers. Increasing the stimulus further does increase the response of whole nerve2. 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.

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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).

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 membraneThe 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.

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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 110In many myelinated number neurons, the Na channels are flanked by K channels that areيحيط 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 shapeEach 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.

• 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.

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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 pointNerve accommodationThe 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 reactionPotassium 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 voltage-gated 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 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

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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). 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.

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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.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

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.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. Some2. Facilitate or inhibit signals3. Postsynaptic neurons respond with large numbers of output impulses, and others respond with only a few numbers of output impulses4. 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 directionGeneral 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 pre-synaptic terminal opens voltage-gated calcium channels and the resulting calcium influx triggers 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

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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

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

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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: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.

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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 developReuptake 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. NeurotransmittersSmall-Molecule, Rapidly Acting TransmittersClass I: Acetylcholine Class II (The Amines): Norepinephrine, Epinephrine, Dopamine, Serotonin, Histamine Class III (Amino Acids): Gamma-aminobutyric acid, Glycine, Glutamate, Aspartate Class IV: Nitric oxideClass 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. 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).

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Destruction of the Released Acetylcholine by AcetylcholinesteraseThe 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:

• 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

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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) DopamineThere 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 5-HT4) 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 retinaSerotonins 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 peristalsis5-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. 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 sleep3. HistamineThere are two receptors (H1, H2)• is formed from histidine.• is present in the neurons of the hypothalamus.

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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- conductanceClass 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 synapsesUniform 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 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)):

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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, 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

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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 EPSP1. 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 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.

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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: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:

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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 IPSP1. 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) 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.

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Summation at synapsesMany 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 occura. Spatial summation occurs when two excitatory inputs arrive at a postsynaptic neuron simultaneously واِحد آٍن .فيIn 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 سريع .توالIn 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.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.33

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 becauseTheir 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 the membrane. This decrease in membrane potential as it spreads electro-tonically along dendrites toward the soma is called decremental conductionThe 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.

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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 TransmissionMany drugs are known to increase the excitability of neurons, and others are known to decrease excitability. For instance, 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 DelayDuring 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

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(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 وابل of 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.

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