Neuron

• The neuron (or nerve cell) is the functional unit of both the central nervous system (CNS) and the peripheral nervous system (PNS).
• The basic functions of neurons can be summarized into three main tasks:
• 1. Receiving signals,
• 2. Integrating these signals and
• 3. Transmitting the signals to target cells and organs.
• These functions reflect in the microanatomy of the neuron. As such, neurons typically consist of four main functional parts which include the:

• Receptive part (dendrites), which receive and conduct electrical signals toward the cell body
• Integrative part (cell body/soma), containing the nucleus and most of the cell's organelles, acting as the trophic center of the entire neuron
• Conductive part (axon), which conducts electrical impulses away from the cell body
• Transmissive part (axon terminals), where axons communicate with other neurons or effectors (target structures which respond to nerve impulses)

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The resting membrane potential

• Imagine taking two electrodes and placing one on the outside and the other on the inside of the plasma membrane of a living cell.
• If you did this, you would measure an electrical potential difference, or voltage, between the electrodes.
• This electrical potential difference is called the membrane potential.

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• Because there is a potential difference across the cell membrane, the membrane is said to be polarized.
• If the membrane potential becomes more positive than it is at the resting potential, the membrane is said to be depolarized.
• If the membrane potential becomes more negative than it is at the resting potential, the membrane is said to be hyperpolarized.

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Where does the resting membrane potential come from?

• The resting membrane potential is determined by the uneven distribution of ions (charged particles) between the inside and the outside of the cell, and by the different permeability of the membrane to different types of ions.

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Types of ions found in neurons

• In neurons and their surrounding fluid, the most abundant ions are:
• Positively charged (cations): Sodium (Na) and potassium (K)
• Negatively charged (anions): Chloride (Cl ) and organic anions
• In most neurons, K  and organic anions (such as those found in proteins and amino acids) are present at higher concentrations inside the cell than outside.
• In contrast, Na  and  Cl are usually present at higher concentrations outside the cell. This means there are stable concentration gradients across the membrane for all of the most abundant ion types.

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Causes of The RMP

• The intracellular and extracellular concentration of Na+ , K+ and Cl- ions are different.
• Also, the permeability of the cell membrane to the individual ions is also different.
• These two factors are mainly responsible for the magnitude of RMP.
• As the cell membrane is freely permeable to K+ ions, K+ tends to move out of the cell along the concentration gradient.
• But, as K+ moves out of the cell, the interior of the cell becomes negatively charged due to loss of cations.

This could have been prevented:

• If the Na+ ions entered into the cell but the cell membrane is impermeable to Na+ ions.
• Protein anions inside the cells could have moved out to neutralize intracellular negativity. But they are too large to pass through the cell membrane.
• Cl- ions also cannot move out of the cell against the steep concentration gradient.
• So intracellular negativity persists.

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• This intracellular negativity will attract the outgoing positively charged K+ ions towards the interior of the cell due to electrical gradient.
• So, two forces act on K+ ions.
• One due to concentration gradient is pushing K+ ions out of the cell.
• The other due to electrical gradient is attracting K+ ions towards the interior of the cell.
• At a particular electrical potential, these two forces balance each other and and equilibrium is established. This is known as equilibrium potential of K+.

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• In contrast to K+ ions, Na+ ions have electrical gradient and concentration gradient both directed to the inside of the cell.
• (As the interior of the cell is electrically negative due to K exit, electrical gradient of cationic Na+ is directed inward.
• Again, as the ECF (Na+) is much higher than intracellular (Na+), concentration gradient of Na+ is directed towards the interior of the cell).

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• So K+ ions tend to move the RMP to its equilibrium potential i.e. -90mV.
• On the other hand, Na+ ions tend to pull RMP in opposite direction to its equilibrium potential, which is +65mV.
• Similarly Cl- try to maintain the RMP at its own equilibrium potential which is -70mV.
• Cl- ion does not have a pump to influence its distribution unlike Na+ and K+ ions.
• So, it cannot influence RMP.
• On the contrary, it is passively distributed in accordance with RMP.

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• Thus, the intracellular negativity of RMP forms an outward electrical gradient repelling Cl- to the cell exterior and producing a high extracellular Cl- concentration.
• This again leads to an inwardly directed concentration gradient of Cl – ions.
• Two gradients balance each other at equilibrium.
• Thus disparity of Cl- ions on two sides of the cell membrane is caused passively by RMP.
• To sum up, Cl- ion, in absence of a Cl – pump, has no active influence on RMP and it is just passively distributed on the two sides of the cell membrane in accordance with RMP.

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• Now, the resultant RMP depends on the permeability or conductance of the individual ions.
• As the K+ ion is 10-25 times more permeable than Na+ ion, the resting membrane potential is much closer to Ek than ENa.
• Actual RMP stands at -70 mV in a nerve cell.

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• It should be noted that at RMP, neither K+ ions nor Na+ ions are at their equilibrium potential.
• So, there is movement of Na+ ions into the cell and K+ ions out of the cell.
• However, this does not alter the intracellular or extracellular Na+ and K+ ion concentration significantly.
• This is because Na+ K+ ATPase pumps constantly pump out Na+ out of the cell and K+ into the cells. This maintains the ionic balance.

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• A small part of the RMP is contributed directly by the electrogenic Na+ K+ ATPase pump which drives out 3 Na+ ions from the cell and brings 2K+ ions into the cell.
• This causes slight intracellular negativity due to loss of cations.

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Action Potential

Definition

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Action potentials are nerve signals. Neurons generate and conduct these signals along their processes in order to transmit them to the target tissues. Upon stimulation, they will either be stimulated, inhibited, or modulated in some way. 

• But what causes the action potential?
• From an electrical aspect, it is caused by a stimulus with certain value expressed in millivolts [mV].
• Not all stimuli can cause an action potential.
• Adequate stimulus must have a sufficient electrocal value which will reduce the negativity of the nerve cell to the threshold of the action potential.

• In this manner, there are subthreshold, threshold, and suprathreshold stimuli. 
• Subthreshold stimuli cannot cause an action potential. 
• Threshold stimuli are of enough energy or potential to produce an action potential (nerve impulse). 
• Suprathreshold stimuli also produce an action potential, but their strength is higher than the threshold stimuli. 

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• So, an action potential is generated when a stimulus changes the membrane potential to the values of threshold potential. 
• The threshold potential is usually around -50 to -55 mV.
• It is important to know that the action potential behaves upon the all-or-none law.
• This means that any subthreshold stimulus will cause nothing, while threshold and suprathreshold stimuli produce a full response of the excitable cell. 

• Is an action potential different depending on whether it’s caused by threshold or suprathreshold potential?
• The answer is no.
• The length and amplitude of an action potential are always the same. However, increasing the stimulus strength causes an increase in the frequency of an action potential.

• An action potential propagates along the nerve fiber without decreasing or weakening of amplitude and length.
• In addition, after one action potential is generated, neurons become refractory to stimuli for a certain period of time in which they cannot generate another action potential.

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Phases

• From the aspect of ions, an action potential is caused by temporary changes in membrane permeability for diffusible ions.
• These changes cause ion channels to open and the ions to decrease their concentration gradients.
• The value of threshold potential depends on the membrane permeability, intra- and extracellular concentration of ions, and the properties of the cell membrane. 

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• An action potential has three phases: 
• depolarization, overshoot, repolarization.
• There are two more states of the membrane potential related to the action potential.
• The first one is hypopolarization which precedes the depolarization, while the second one is hyperpolarization, which follows the repolarization.

Ions exchange in action potential (diagram)

Ions exchange in action potential (diagram)

Ions exchange in action potential (diagram)

• Hypopolarization is the initial increase of the membrane potential to the value of the threshold potential.
• The threshold potential opens voltage-gated sodium channels and causes a large influx of sodium ions.
• This phase is called the depolarization. During depolarization, the inside of the cell becomes more and more electropositive, until the potential gets closer the electrochemical equilibrium for sodium of +61 mV.
• This phase of extreme positivity is the overshoot phase.

• After the overshoot, the sodium permeability suddenly decreases due to the closing of its channels.
• The overshoot value of the cell potential opens voltage-gated potassium channels, which causes a large potassium efflux, decreasing the cell’s electropositivity.
• This phase is the repolarization phase, whose purpose is to restore the resting membrane potential.

• Repolarization always leads first to hyperpolarization, a state in which the membrane potential is more negative than the default membrane potential.
• But soon after that, the membrane establishes again the values of membrane potential.

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• After reviewing the roles of ions, we can now define the threshold potential more precisely as the value of the membrane potential at which the voltage-gated sodium channels open.
• In excitable tissues, the threshold potential is around 10 to 15 mV less than the resting membrane potential.

Refractory period

• The refractory period is the time after an action potential is generated, during which the excitable cell cannot produce another action potential.
• There are two subphases of this period, absolute and relative refractoriness. 

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• Absolute refractoriness overlaps the depolarization and around 2/3 of repolarization phase.
• A new action potential cannot be generated during depolarization because all the voltage-gated sodium channels are already opened or being opened at their maximum speed.
• During early repolarization, a new action potential is impossible since the sodium channels are inactive and need the resting potential to be in a closed state, from which they can be in an open state once again.
• Absolute refractoriness ends when enough sodium channels recover from their inactive state.

• Relative refractoriness is the period when the generation of a new action potential is possible, but only upon a suprathreshold stimulus.
• This period overlaps the final 1/3 of repolarization. 

Propagation of action potential�

• An action potential is generated in the body of the neuron and propagated through its axon.
• Propagation doesn’t decrease or affect the quality of the action potential in any way, so that the target tissue gets the same impulse no matter how far they are from neuronal body.

• The action potential generates at one spot of the cell membrane.
• It propagates along the membrane with every next part of the membrane being sequentially depolarized.
• This means that the action potential doesn’t move but rather causes a new action potential of the adjacent segment of the neuronal membrane.

• We need to emphasize that the action potential always propagates forward, never backwards.
• This is due to the refractoriness of the parts of the membrane that were already depolarized, so that the only possible direction of propagation is forward.
• Because of this, an action potential always propagates from the neuronal body, through the axon to the target tissue.

• The speed of propagation largely depends on the thickness of the axon and whether it’s myelinated or not.
• The larger the diameter, the higher the speed of propagation.
• The propagation is also faster if an axon is myelinated.
• Myelin increases the propagation speed because it increases the thickness of the fiber.

• In addition, myelin enables saltatory conduction of the action potential, since only the Ranvier nodes depolarize, and myelin nodes are jumped over. �
• In unmyelinated fibers, every part of the axonal membrane needs to undergo depolarization, making the propagation significantly slower. 

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All- or- non law

• Once the intensity of stimulus has reached threshold level, the amplitude of the action potential will remain the same, irrespective of any increase in the intensity of stimulus.
• Thus, stimulus of higher intensity will not cause any increase in the amplitude of action potential.
• As the same time, it should be noted that it the intensity of the stimulus falls below threshold value, no action potential will result. That is why this is known as all-or-none law.

Synapse

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1. Definition

• The junction between two neurons is called a synapse.
• It is a specialized junction where transmission of information takes place between a nerve fibre and another nerve, muscle or gland cell.
• It is not the anatomical continuation. But, it is only a physiological continuity between two nerve cells.

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2. Structure

The synapse consists of:

1. A presynaptic ending that contains neurotransmitters, mitochondria and other cell organelles.

2. A postsynaptic ending that contains receptor sites for neurotransmitters.

3. A synaptic cleft or space between the presynaptic and postsynaptic endings. It is about 20nm wide.

• Function
• The main function of the synapse is to transmit the impulses, i.e. action potential from one neuron to another.
• They allow integration, e.g. an impulse travelling down a neuron may reach a synapse which has several post synaptic neurons, all going to different locations. The impulse can thus be dispersed. This can also work in reverse, where several impulses can converge at a synapse

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Types

Synapses are usually classified as follows.

1. According to the part of neuron involved.

• Axo-dendritic- axon with dendrite.
• Axo- somatic- axon with cell body (soma)
• Axo- axonic- axon with axon.
• Dendro- dendritic- dendrite with dendrite.

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2. According to the nature of transmission

Chemical synapse – through neurotransmitter

• In a chemical synapse, electrical activity in the presynaptic neuron is converted into the release of a chemical called a neurotransmitter that binds to receptors located in the plasma membrane of the postsynaptic cell.

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Electrical synapse – through gap junctions.

• In these synapses the membranes of the two cells actually touch, and they share proteins. This allows the action potential to pass directly from one membrane to the next. They are very fast, but are quite rare, found only in the heart and the eye.
• Conjoint synapse – partly electrical and partly chemical

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3. According to the number of neuron involved

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• One neuron ends on another (one to one)
• Multiple neurons ending on a single neuron (many to one)
• One neuron ends on multiple neurons (one to many)

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• Convergence refers to the phenomenon of termination of signals from many sources (i.e. many pre-synaptic neurons on a single post-synaptic neuron).
• Divergence refers to one pre-synaptic neuron terminating on many post-synaptic neurons. (i.e. single impulse is converted into a number of impulses going to a number of post-synaptic neurons.)

• Chemical synapse:
• Majority of synapses are of this type. Here synaptic transmission needs chemical mediators.
• The neuron from which the information passes through the synapse is called presynaptic neuron and the neuron which receives the information is called post synaptic neuron.
• The part of presynaptic neuron forming the synapse is called presynaptic membrane and that of the post synaptic neuron is called the post synaptic membrane.

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• The synapse is thus formed by the presynaptic membrane, postsynaptic membrane and the synaptic cleft in between them.
• The synaptic cleft is the gap in between these two membranes and is about 20 -50 nm wide.
• The presynaptic membrane is usually the part of an axon terminal, also called synaptic knob. Which contains neurotransmitter.

• It shows thickening called active zone which contain voltage gated Ca²⁺channels along with other proteins related to transmitter release.
• The postsynaptic membrane may be a part of dendritic spine, part of a cell body (soma) or part of an axon of neuron ( and in some cases muscle and gland cells), which contain receptors for the neurotransmitter. Sometimes it shows thickening called post synaptic density which contains receptors, binding proteins etc.

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• Neurotransmitter: is the chemical substance which is used to transfer of information through the synapse.
• This neurotransmitter amplifies the effect of the AP coming to the synapse.

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• Only due to this amplification the AP in the presynaptic neuron can stimulate the post synaptic neuron. Otherwise the AP, through usual way of conduction (I. e by local current) would not be able to depolarize the postsynaptic membrane after passing through the synaptic cleft.

• The arrangement in the synapse is such that the neurotransmitter can act on an wide area of the post synaptic membrane and a large number of receptors (ion channels) are activated.
• The protein neurexins in the presynaptic membrane help a lot to maintain the normal activities of a synapse.

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Synaptic transmission:

• It is the process by which the information passes through release of neurotransmitter.
• When an AP comes along the axon of presynaptic neuron it increases Ca²⁺ entry from the ECF into the synaptic knob through voltage gated Ca²⁺ channels.
• Increased Ca²⁺ in the synaptic knob leads to exocytosis of the neurotransmitter stored in the vesicles in the synaptic knob.

• The proteins called neurexin influence the synaptic activity and also help to hold the synapses together.
• The released transmitter now crosses the synaptic cleft by diffusion and binds to large number of its receptors on the postsynaptic membrane.
• These receptors are ligand gated ion channels. After the binding, ion channels in the receptors open up and movement of ions occurs.

• Depending upon the (Cation or Anion) and direction of their movement, the membrane potential MP of postsynaptic membrane changes either towards depolarization or hyperpolarization.
• This change of MP, also called synaptic potential creates the signal in post synaptic neuron.

• AP in the presynaptic ending entry of Ca²⁺in the synaptic ending release of neurotransmitter binding with receptors on the postsynaptic membrane opening of the ion channels movement of ions through the postsynaptic membrane change of MP in the postsynaptic membrane (synaptic potential)

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Synaptic potential may be of two types

• Excitatory postsynaptic potential (EPSP)
• Inhibitory postsynaptic potential (IPSP)

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• Synaptic potential is of longer duration than an action potential and if it is excitatory, can cause repeated firing of the initial segment of the postsynaptic neuron.

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• Electrical synapse
• This type is formed through gap junction, through which electrical activities of one neuron can pass to the other directly.
• This is found between some neuron in the lateral vestibular nucleus, neocortex and cerebellum etc. in chemical synapse the transmission is usually unidirectional.
• An electrical synapse may be bidirectional and transmission is fast.

• Slow electrical events are also easily transmitted by them.
• As stated above due to magnification of signal, the chemical synapses are superior to the electrical synapses in the nervous system.
• One to one synapse is the neuromuscular junction, many to one is the usual type found in CNS and one to many is not frequent .
• One to one synapse is typical of parasympathetic and one to many types are found in sympathetic system.

Properties of synapse

• The synapses or rather the synaptic transmission shows the following properties.

1. Law of forward conduction:

• Through a synapse impulse can travel in one direction only i.e., from pre to postsynaptic neuron(exception electrical synapse). This is called law of forward conduction.

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2. Synaptic delay

• Transmission in the synapse suffer a delay.
• This synaptic delay is the time required for the impulse to cross the synapse.
• It is about 0.5 ms. This time is required for Ca²⁺entry in the presynaptic knob, release of neurotransmitter and for its action on the postsynaptic membrane.
• The knowledge about synaptic delay helps to find out the number of synapses present in neural pathway.

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3. Law of divergence and convergence

• Through the synapses, information from one neuron can pass to many neurons and from many neurons information can pass to a single neuron. These are respectively called divergence and convergence.

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4. Excitatory postsynaptic potential(EPSP):

• If the potential change in the postsynaptic membrane due to synaptic transmission is towards depolarization then it is called EPSP, e.g. initially the RMP was -70 mV, after transmission it becomes say, -60mV, so the EPSP = 10 mV. EPSP of optimum magnitude leads to excitation (AP formation) of postsynaptic neuron.
• EPSPs are caused by transmitters like acetylcholine, nor adrenalin etc.
• Ionic basis: the neurotransmitter causing EPSP increases permeability of the postsynaptic membrane to various cations through its receptor. For example, acetylcholine receptors allow Na+ entry and K+ exit.

5. Inhibitory postsynaptic potential (IPSP)

• Due to synaptic transmission, if the potential of postsynaptic membrane is carried towards hyperpolarization, then it is called IPSP.
• This is because the hyperpolarization leads to inhibition of the postsynaptic neuron.
• Suppose the RMP was -70 mV, after transmission it becomes say -80 mV, so IPSP = 10 mV.

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Ionic basis Here the neurotransmitter usually causes opening of Cl^- channels and entry of Cl^- leads to hyperpolarization of the postsynaptic membrane, this carries the MP away from the firing potential and thus causes inhibition. An increase of K⁺efflux, a decreased N⁺ or Ca²⁺influx will lead to IPSPs

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Neurotransmitters

• Neurotransmitter is a type of chemical messenger that transmits signals across a chemical synapse, from one neuron to another.

Types of Neurotransmitter

• There are the following different types of neurotransmitter:

Excitatory Neurotransmitters

• These type of neurons increase the chances of the neuron firing an action potential.
• Epinephrine and norepinephrine are the two excitatory neurotransmitters.

Inhibitory Neurotransmitters

• These have inhibitory effects on the neurons and have fewer chances of the neuron firing an action potential.
• For eg., serotonin and gamma-aminobutyric acid (GABA).

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• Neurotransmitters of the PNS and CNS
• Neurotransmitters present in the peripheral nervous system  (PNS) are acetylcholine (ACh), norepinephrine, and epinephrine.
• In the central nervous system (CNS), a variety of chemicals act as neurotransmitters, including ACh, amines, serotonin, dopamine, norepinephrine, epinephrine, glutamate, aspartate, glycine, γ‐aminobutyric acid (GABA), peptides, and nitric oxide  (Table  3.1).

• Acetylcholine is synthesized from choline and acetyl coenzyme A (acetyl‐CoA) in the axon  terminal.
• Neurons that release ACh are called cholinergic neurons.
• The amine neurotransmitters (e.g., dopamine, norepinephrine, epinephrine, serotonin, histamine, tyrosine) are derived from amino acids.

• Dopamine, norepinephrine, and epinephrine are synthesized from tyrosine.
• Neurons that release norepinephrine or epinephrine are called adrenergic neurons.
• Serotonin (or 5‐hydroxytryptamine or 5‐ HT) is derived from the amino acid tryptophan and histamine from histidine.
• Glutamate and aspartate are the excitatory neurotransmitters of the CNS.

• The primary inhibitory neurotransmitters in the CNS are GABA and glycine.
• Peptides that act as neurotransmitters include substance P and opioid peptides such as enkephalins and endorphins.
• Substance P is involved in pain pathways and enkephalins and endorphins mediate analgesia.

• An unusual neurotransmitter, nitric oxide (NO), diffuses freely into the target neuron to bind to intracellular proteins.
• Nitric oxide is synthesized from oxygen and the amino acid arginine.

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• Neurotransmitters are removed quickly from the synaptic cleft after detaching from their receptors.
• This involves at least two processes:
• (i) enzymatic inactivation in the synaptic cleft and
• (ii) diffusion away from the synaptic cleft. Enzymatic inactivation in the synaptic cleft is followed by subsequent uptake of constituents by the presynaptic terminal for resynthesis of neurotransmitter

• For example, ACh released into the synaptic cleft attaches to postsynaptic receptors and quickly detaches before being broken down to choline and acetate by acetylcholinesterase (AChE) present on the postsynaptic membrane (Figure 3.2A).

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Figure Synthesis and recycling of the excitatory neurotransmitters acetylcholine (ACh)

Figure 3.2 Synthesis and recycling of the excitatory neurotransmitters glutamate.

• Choline is actively transported back into the presynaptic terminal for resynthesis of more ACh neurotransmitter.
• The other process for removing neurotransmitters from the synaptic cleft is diffusion.

• This allows neurotransmitters to enter the circulation or be transported back into the neuron or into astrocytes.
• For example, glutamate is transported back into the presynaptic terminal or astrocytes.
• In the presynaptic terminal, glutamate is repackaged into synaptic vesicles.

• In the astrocytes, glutamate is converted to glutamine by glutamine synthetase.
• Glutamine is then transported to the presynaptic terminal by glutamine transporters, and it is repackaged into synaptic vesicles to be used as neurotransmitter.

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Degeneration and regeneration of nerve fibre

• Damage to nerve cell bodies or their processes can either lead to rapid necrosis with sudden acute functional failure, or to slow atrophy with gradually increasing dysfunction.

These changes are associated with

• Hypoxia and anoxia
• Nutritional deficiencies
• Poisons eg. organic lead
• Trauma

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• Infection
• Ageing
• Hypoglycaemia
• Neuron of the brain, spinal cord and ganglia reach maturity a few weeks after birth and are not normally replaced when they are damaged or die.
• The axons of peripheral nerves may regenerate if cell body remain intact.

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• Distal to the damage, the axon and myelin sheath disintegrate and are removed by macrophages, but the Swann cells survive and proliferate within the neurilemma.
• The live proximal part of the axon grows along the original track (about 1.5 mm per day), provided the two parts of neurilemmal are correctly positioned and in close apposition.

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• Distal to the damage, the axon and myelin sheath disintegrate and are removed by macrophages, but the Swann cells survive and proliferate within the neurilemma.
• The live proximal part of the axon grows along the original track (about 1.5 mm per day), provided the two parts of neurilemmal are correctly positioned and in close apposition.

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• Restoration of function depend on the re-establishment of satisfactory connections with the end organ.
• When the neurilemmal is out of position or destroyed, the sprouting axon and swann cell form a tumour like cluster (traumatic neuroma) producing severe pain e.g. following some fractures and amputation of limbs.

Major functions of nervous system

• Major functions of the nervous system are:
• Reception of general sensory information (touch, pressure, temperature, pain, vibration)
• Receiving and perceiving special sensations (taste, smell, vision, sounds)
• Integration of sensory information from different parts of the body and processing them
• Response generation

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