STRUCTURE OF NEURONS
2. STRUCTURE OF NEURONS
We know that multicellular organism, dependent on predefined coordination of individual cells. The neural system is the most important system for rapid coordination in Body of an individual.
Neurons communicate the information using a combination of chemical signals.
Mostly neurons carry out electric signal, that is generated across the plasma membrane of these cells and along the length of the cell without losing the strength of the signal.
Along with neurons, some supporting cells are present called glial cells. glia cells are also called as "neuroglia" Glia (= glue) , that support, nourish and protect neurons glial cells are non-neuronal cells formed from the neural crest.
"Types of Glial cells"
1. Schwann cells are principal glia of P.N.S. (Peripheral nervous system) named after physiologist "Theodore Schwann.
There are two types of Schwann cells, Myelinating & non-myelinating. Myelinating-Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath.
Schwann cells are known for their role in supporting Nerve regeneration. Nerve that present in PNS are made up of axons that are myelinated by Schwann cells. If damage occur in nerve, Schwann cell digest that axons (phagocytosis).
Location of Schwann cells.
Formed in PNS that is around nerves of extremities of the body. e.g. in skin. In "multiple sclerosis", axons of CNS loss their myelin sheaths and there is also death of oligodendrocytes.
2. Oligodendrocytes. - located at central nervous system. Their main function are to provide support and insulation to axon in the CNS of some vertebrates. Like Schwann cell, oligodendrocytes also perform some function of forming myelin sheath.
Schwann cells form the myelin sheath in the PNS while oligodendrocytes form myelin sheath in the CNS.
Microglial cells located throughout the brain and spinal cord. Microglia are 10-15% of all total cells formed within Brain, they are macrophages of CNS or act as a first and main form of active immune defence.
Astrocytes :- star-shaped cells which are present In brain and spinal cord. They perform various function. Including biochemical support of endothelial that form the blood-brain barrier, maintenance of extracellular balance, some astrocytes also signal through calcium Ion dependent release of glutamate. They are the most abundant glial cells in the brain that are closely associated with neural synapsis.
Structure and function of neurons.
Different regions of the neurons are characterized by specialization within the plasma membrane. Neurons vary greatly in shape and size. Each neuron typically has a soma or cell body which is responsible for the metabolism of the cell. Many nerve processes arise from the soma.
There are two main types of processes.
1. Multiple dendrites
2. Single axon(mostly)
1. Dendrites: These are extensions from Soma which are mostly branched and act as receivers that collect the signals from other neurons and carry them towards the cell body.
2 Axon: Axon was also known as nerve fibre. Axons are extensions that conduct signal away from Soma. At the termination of Axon, typically nerve endings divide into numerous branches called axon terminals. Some axons are remarkably very long e.g. in a whale, the Axon of single dorsal root ganglion neuron, which carries information from CNS to the skin of several meters.
Some well-known Neurotransmitters :
i. Neurotransmitters of vertebrate motor neurons.
ii. It is broken down by acetylcholinesterase during signal transfer. Several neurotoxic blockers of these Enzymes are poison.
A. Nor-epinephrine: it causes the gut muscle to relax and heart to beat fast.
B. Dopamine: A neurotransmitter of CNS over-activation of which is involved in schizophrenia. Loss of dopamine in neurons causes paralysis disease.
C. Histamine : A minor neurotransmitter in brain.
D. Serotonin: A neurotransmitter of CNS involved in including pain control, sleep and take control, and mood, the certain medication that elevates mood & counter anxiety act by inhibiting the re-uptake of serotonin.
ATP. - co-released with many neurotransmitters.
Adenosine - transported across the cell membrane.
4. Amino acids:-
1) Glutamate - Most common excitatory neurotransmitter in CNS.
2) Glycine - GABA (gamma amino butyric acid) common inhibitory neurotransmitter.
c) Substance 'P' - used by certain sensory nerves especially in the pain pathway.
Neurons: properties (coordination of nerve impulse):–
The cells are extremely negative from inside and positive from outside. And the positive and negative charge across the plasma membrane produce the difference in potential called as membrane potential. In resting neurons, this voltage difference is known as the resting potential. Membrane potential is measured from with the help of electrode. A neuron is sensitive to chemical or physical factor that causes a change in resting potential across its plasma membrane. The action potential is a rapid change in voltage across the position of the plasma membrane. For 2 milliseconds, an electric current cross membrane and inside of cell become more positive then outside. The nerve impulse is 'action potential' that move along axons.
Ion Pumps and action potentials:-
The plasma membrane of neurons like those of other cells is lipid bilayer i.e., impermeable to ions. Bilayer contains many proteins that act as Ion channel and Ion pumps. The pumps and channels are responsible for resting and action potential. Ion pumps use energy to move ions or other molecules against the concentration gradient. Most common pump found in the plasma membrane of the nerve cell is sodium Potassium pump. This pump expels sodium ions from inside the cell and in return potassium ion from outside to inside. Sodium-Potassium pump keeps the concentration of potassium ion inside the cell greater than the extracellular fluid and concentration of sodium inside the cell less than of extracellular fluid. The concentration differences established by pump means that potassium ion would diffuse out of the cell and sodium ion would diffuse inside if ion could cross the lipid bilayer membranes.
The Ion channels in the plasma membrane are generally selective and they allow only some type of ion to pass. They are
1) potassium ion channel
2) sodium Ion channel
3) chloride Ion channel
4) calcium Ion channel
The potassium ion channel is the most common open channel in the plasma membrane of resting neurons (non-stimulated). Due to the opening of the potassium ion channels, these resting neurons more permeable to potassium ion than to any other ion. As we know that sodium Potassium channel makes the higher concentration of potassium inside the cell, therefore, potassium ion continuously leaks out. As positively charged potassium ion diffuses out of cell they leave unbalanced negative charges ( mostly chloride ions and protein molecules) generating an electric potential across the membrane that tends to pull positive charged potassium ion back inside the cells. The membrane potential at which the tendency of potassium ion to diffuse out of the cell is balanced by the negative electric potential pulling them back inside the cell is called potassium equilibrium potential.
Voltage-gated channels open and close in response to change in the voltage across the plasma membrane. Chemically gated channels open and close depending on the presence or absence of a specific molecule that binds to the channel protein. Both voltages gated and chemically gated channels play important role in neural function
The actual concept of neuron transmission across the axon
The position of ligand and voltage-gated ion channels in the Neuron.
When neurons receive any stimulus in resting state then first of all ligand-gated channels are open. Sodium ions enter the cell body of neurons and then slowly cell become polarized to the threshold level. e.g. the potential difference of inner membrane of neurons become -70 millivolts to -63 millivolt and so on. A very interesting ion channel i.e. leaky potassium channel is open all the time to which potassium ions enter in the axoplasm. Again another shot sodium ions enter in the cell body and then the potential difference becomes more positive.
In a very short time, approximately 2 milliseconds the plasma membrane of neurons becomes depolarize. An action potential is a sudden and major change in membrane potential that lasts for only 1 or 2 milliseconds. The speed of action potential conducted across a membrane is up to a hundred meters per second. As the more and more sodium ions enter in the cell, the potential of the inner membrane reaches up to + 20 millivolts because of more and more opening of sodium channels (voltage-gated sodium channels).
Voltage-gated potassium channels are close, as the potential become + 20 millivolt on the Axolemma ligand-gated sodium channels becomes inactivated. This inactivation of sodium channel activates the opening of the potassium ion channel. As the potassium channels open potassium ion come outside of the cell. The potassium ion come out of cell till potential difference becomes -90 voltage (hyperpolarization state)
1) Absolute refractive period:- The time during which an excitable membrane cannot generate an action potential in response to Any stimulus.
2) Relative refractive period:- Time during which excitable membrane will produce action potential only to a stimulus of greater strength than the usual threshold strength.
Inhibitory and excitatory transmission by neurotransmitters:-
EPSP- (excitatory postsynaptic potential)
Acetylcholine is an excitatory chemical. Neurons that secrete acetylcholine are called cholinergic neurons.
As the Acetylcholine is secreted from nerve endings it acts as a ligand and opens the sodium ion channel. As the sodium enters the cell body, it excites the neurons. This phenomenon is called EPSP.
IPSP- (Inhibitory postsynaptic potential)
GABA (Gamma's aminobutyric acid) and glycine are acting as inhibitory neurotransmitters.
As the glycine and GABA act on ligand-gated potassium and chlorine channel, the chlorine ion enter the cell and cell became more negative i.e. hyperpolarised and signal stops. This phenomenon is called as IPSP.
Nerve transmission at synaptic neuron.
At nerve ending both voltage-gated sodium and voltage-gated calcium channels are present. As the potential difference in ending become -55 from -70 millivolt, Calcium channels are open. Calcium channel is activated and open at -53 millivolts and some ions enter in a nerve ending. As the calcium ions enter the neurons, neurotransmitter-filled vesicles, are released through exocytosis to outside the cell. This released neurotransmitter is maybe of either excitatory or inhibitory. Further, these neurotransmitters act on ligand-gated Ion channels and the transmission of signal starts.
Types of Neurotransmitters
All or none concept :
Nerves and muscles function on the principle of all or none concept. If an action potential is generated and reached at postsynaptic neurons then the transmission is said to have occurred. This is called 'all'.
If an action potential is failed to generate impulse conduction then no nerve transmission occurs. Then it is called as 'none'.
If Ratio of the threshold for excitation is greater than 1 then propagation takes place. That means, any stimulation which has greater strength than the strength of threshold, will give a complete response.
Action potential initiated into neurons when EPSP increased enough positive direction. Action potential generates at the point where axon leaves neuronal Soma. Soma has very less number of voltage-gated sodium Ion channels due to which EPSP not able to begin action potential.
Propagation of action potential.
Some neurons are so small that electronic conduction is sufficient for their needs. Some cells are incapable of producing an action potential. Therefore referred to as non-spiking neurons. In this non-spiking cells, the amplitude of the signal is attenuated as they spread through the cell but the signals are still large enough at the terminals to modulate the release of neurotransmitters. Non-spiking cells are incapable of producing action potential but capable in the release of neurotransmitters.
They are found in the vertebrate retina and other parts of vertebrate CNS, the barnacle eye, the insect CNS and crustacean soma so gastric ganglion. Non-spiking neurons are very few millimetres in overall length and they are generally characterized by high specific membrane resistance.
Some elements are capable to produce action potential at a single point in excitable cells. In order to carry information, these events must be regenerated i.e. they must take place over and over again along the axon without decrement. An action potential travels along an axon membrane and excites neighbouring patches.
The action potential is typically produced by two classes of ion channels selective for Sodium ion and the other selective for potassium ion. At the initiation of an A.P., voltage-gated sodium Ion channels open increasing the permeability of the plasma membrane of sodium ion. When the sodium Ion channels open, sodium ions carry a large and transient current into the axon. This inward current spreads longitudinally along the axon and then leaks out across the membrane to complete the circuit of current flow. This electronic flow or spread of current away from active patches of the membrane is crucial for the propagation of an action potential.
When positively charged ion enters the neurons through open sodium Ion channel, the potential difference across the membrane become less negative. These changes cause charge group near the neighbouring region of the membrane to move. The positive charge in the cytosol are pushed away from the open channels and positive charges in the extracellular fluid are towards the outside mouths of the open channel. As results, the patch of axonal membrane that is immediately ahead of the potential, partially depolarise.
The membrane just ahead of the impulse becomes depolarize by these local current voltage-gated sodium channel and that portion of the membrane cross threshold potential and initiating an action potential is this new patch of membrane. The newly excited region generates the local current that depolarizes and thereby excited the region of axon just ahead of them. This mechanism is initially recognized by Alan Hodgkin.
The amount of depolarization required to bring a patch of the inactive membrane to the active stage is about 20 millivolt, where the total depolarization during an action potential is typically about 100 millivolt. The membrane all along the axons undergoes some depolarization. Thus an action potential produces an approximately fivefold boost of the electronic signal along the axon. The energy for this amplification is derived from the unequal concentration of sodium Ion inside and outside the membrane. If an axon has been stimulated somewhere in the middle of its length, the action potential propagates in both direction away from the point of stimulation. However, in a nervous system, backwards moving current normally cannot be produced. A backward travelling action potential ceased because the membrane just behind a region of advancing excitation is in a refractory state.
Speed of propagation
Johannes Miller, a leading 19th-century physiologists declared in 1830 that velocity of the action potential would never be measured. He responds that action potential, being an electrical impulse must travel at the speed of the light. Too fast to resolve over biological distance even with the best instrument available at that time but the ionic process is much slower than the movement of electrons through a wire.
Within 15 years, one of the millers own student Von Helmholtz, had measured the velocity of impulse regulation in frog nerves in an experiment using frog nerve-muscle preparation. Helmholtz stimulated a nerve at two locations of three centimetres apart and measured the latency to the peak of the muscle twitch.
Suppose that the latency increased by 1 MS when the stimulating electrode is moved from location 1 to location 2. The velocity up propagation of can is calculated as the formula.
Rapid saltatory coordination in myelinated axon :
Oligodendrocytes and Schwann cells are wrapped around segments of the axon to produce a layer of fatty membranes collectively called myelin.
This fatty layer has two effects on the cable properties of neurons.
1) They increase the effective transmembrane resistance.
2) They decrease the effective membrane capacitance.
The resistance between the cytoplasm and extracellular fluid increases with the number of membrane layers wrapped around the axon, maybe as many as 200. The capacitance decrease because the myelin layer is very thick. Myelin sheath actually not improve coordination if it completely covered axon. Because the electronically conducted current would still eventually decrease to 0 as a function of distance. Instead, the myelin sheath segmented each segment typically about 100 times the external diameter of the axon, ranging from 200 mm to 2 MM. The myelinated regions are separated by short unmyelinated gaps called Nodes of Ranvier at which about 10 mm (micrometre) of the axon is exposed to the extracellular fluid
The region of the axon that lies under myelin wrapping is called internodes.
In the course of development, myelin is laid down around the axons of vertebrates by two kinds of glial cells
1) Schwann cells in the peripheral nervous system
2) Oligodendrocytes in the central nervous system
Between Nodes of Ranvier, the myelin sheath is so thick snug that it nearly eliminates the extracellular space surrounding the axonal membrane.
The intermodal axonal membrane has been formed to lack voltage-gated sodium Ion channels and potassium ion channels, thus when a local current flow in advance of the action potential it exit the axon almost exclusively through the Nodes of Ranvier.
Very little current is expanded in discharging membrane capitals along the internodes because the capitals of the thick myelin sheath are low.
An action potential that initiates at first node extremely depolarize the membrane at the next node, thus in myelinated axons, action potential does not propagate continuously along the axonal membrane as they do in non-myelinated nerve fibres. Instead, action potentials are only in small area of membrane exposed at the Nodes of Ranvier. The results are saltatory co-ordination, a series of discontinuous and regulator depolarization that take place only at the Nodes of Ranvier. The velocity of signal transmission is greatly enhanced as electronic local current spread along internodal segments. The nervous system of all vertebrates includes both myelinated and non-myelinated neurons. Typically a single nerve contains many myelinated axons of different diameters as well as layer number of myelinated fibres.
As a result, signal travel along a single nerve at many different velocities. axons typically can be sorted in two distinct groups and the axons within each group carry classes of information.
interestingly, c-fibres which carry signals are among the smallest and shortest.
The coordination velocity of myelinated fibres varies from few metres per second to more than 120 metres per second, while myelinated fibres of similar diameter conduct at an action of a metre per second.
Transmission of information between neurons.
All information process done by neurons is dependent on the transmission of the signal from one neuron to another which is completed at a structure called synapse At the electrical synapse, the pre-synaptic neurons are electrically connected to postsynaptic neurons by proteins within the membrane. Transmission across electrical synapsis proceeds very normally like signal transmission along a single axon. However, electrical synapses are relatively rare.
Maximum signalling between neurons takes place at chemical synapses.
At chemical synapses, the action potential in presynaptic neurons causes the release of neurotransmitter molecule that diffuse across a narrow space( about 20 NM wide), called the synaptic drift that separates the membranes of pre and post-synaptic neurons.
A handful of chemicals known to be synaptic neurotransmitters and synaptic transmission was thought to resemble transmission at neuromuscular Junction (synapse that connects motor neurons and skeletal muscle fibre). Today more than 50 neurotransmitters have been identified in many various organs. Early in the 20 century, the Great histologist "Santiago Ramon Y Cajal" used light microscope and silver based staining technique developed by the neuroanatomist " Camillo Golgi" to show that neurons are discrete units, but this evidence was not immediately accepted.
After the discovery of the electron microscope in 1940, unequivocal evidence was obtained that neurons are indeed separate from one another and that particular region of neurons are specialized for communication between cells.
Synapses( greek-to clasp)
Founder of modern neurophysiology - (Sir Charles Sherrington)
Synaptic structure and functions:-
Electrical synapses transfer information between cells by direct ionic coupling.
At electrical synapses, the plasma membrane of the pre and postsynaptic cells are in close proximity and communication between cells take place by a way of protein channels called gap Junction.
Ions can flow directly from one cell to the another through gap junctions. So an electrical signal in the presynaptic cell produces a similar, although somewhat attenuated, signal in the postsynaptic cell by simple electronic conduction through the junction.
Single transmission cross chemical synapses are always slower than purely electrical signal transmission. Electrical transmission can be illustrated experimentally by injecting current into one cell, measuring the effect in the connected cell. When a current pulse is injected into cell 'A', it increases the transient change in the membrane potential of that cell. If enough of the current injected into cell A, it spreads through gap Junction into cell B where it will cause a detectable change in the potential of cell B as well.
There is a potential drop as the current cross the gap junctions, so the potential change record across the membrane of cell b will always be less than that recorded cell A. Current generally flows through gap Junction equally in either direction. At some electrical synapses, however ionic current flow more readily in one direction than the other. Such junctions are called as "Rectifying".
The transmission of an action potential through an electrical synapse is basically no different from propagation along the single axon because phenomenon depends on the passive spread of local current ahead of action potential depolarize and excite neighbouring region. Although at an electrical synapse, the potential at the postsynaptic cell is smaller than the potential at the presynaptic cell. Electrical synapse provides low flexibility in synaptic transmission, which may be one evolutionary region why they are less common than chemical synapse.
Electrical transmission first of all discovered in 1959 by "Edwin J. Furshapan" and "David D Potter", who were studying the nervous system of the crayfish.
Electrical transmission is discovered in many locations for example
1 in the vertebrate retina
2 vertebrates central nervous system
3 between smooth muscles fibres
4 between cardiac muscle fibres
5 between sensory receptor cells
These electrical synapses are also effective for rapidly transmitting information series of Cell to cell Junction.
At some synapses, transmission is both electrical and chemical. These synapses are called combined synapse.
Combined synapse was first identified in the cells of avian ciliary ganglion.
Combined synapse appear often in the animal having the best of both kinds of transmission.
They are also found in the circuit controlling the fish escape response and in some spinal inter-neurons of the company (fish).
Synaptic structure and functions of chemical synapses.
Chemical synaptic transmission is found at neuromuscular Junction at many synapses in neurons. Although this transmission is called fast it is in fact considerably slower than transmission across the electrical synapse.
When an action potential travels down an axon & spreads into the axon terminals, neurotransmitter molecules that are bound in membrane-bounded spheres, called synaptic vesicle, are released by exocytosis into the synaptic cleft.
The liberated neurotransmitter molecules diffuse across the cleft and bind to specific protein receptor molecules in the postsynaptic membrane, opening ligand-gated Ion channels.
The open channel allows a brief ionic current to flow through the membrane of the postsynaptic cell. This mechanism is the basis for first chemical synaptic transmission in all animals. The earliest direct evidence for a chemical transmitting substance was obtained by " Otto Loewi" in 1921. When he electrically stimulated the vagus nerve, the heart rate slows down. By a close look, he found that in this process, a substance was released into the surrounding saline solution that could cause a second frog heart to beat more slowly, too.
Leowi's finding the lead to the discovery that acetylcholine is the transmitter substance released by postganglionic neurons of PNS in response to stimulation of the vagus nerve, as well as by motor neurons involving skeletal muscles in vertebrates.
Both physiological and anatomical evidence indicates that a single presynaptic neuron may participate in both kinds of chemical neurotransmission. i.e. fast and slow transmission. Such neurons have some transmitter substances which typically produce fast transmission while another produce slow transmission.
In both fast and slow chemical synaptic neurotransmission, the transmitter molecules are packed in vesicles in the presynaptic terminal and are released by exocytosis.
Slow chemical transmission :
The neurotransmitters used in slow transmission are packed in larger vesicles and are typically synthesized from one or more amino acids. They are called as Biogenic amines if they contain a single amino acid or neuropeptides consists of several amino acid residues. They are formed in cyton body and packaged into large vesicles, are transported to axon terminals. As the name implies, the onset of the postsynaptic response sit can last much longer (from seconds to hours). The release of neurotransmitter into the synaptic cleft is a mechanism that is common to both fast and slow chemical transmission. Action potential arrives at axon terminal, it activates voltage-gated calcium channel in the plasma membrane of axon terminal allowing calcium ions to enter in axon terminal.
The increased concentration of calcium ion cause exocytosis of the vesicles containing the transmitter, pouring transmitter molecules into the synaptic cleft, where they diffuse away from the presynaptic terminal. Neurotransmitter containing synaptic vesicles fuse with the plasma membrane and release their specialized site called action zone.
The vesicles that mediate slow synaptic transmission release their transmitter molecule at many sites in the presynaptic terminal. This transmission is slow because neurotransmitter first binds to a receptor protein on the postsynaptic membrane. It causes the release of another intracellular transmitter that further bind to ion channel causing its opening. Neurotransmitters effect postsynaptic cells by modifying ionic current traversing the postsynaptic membrane, hence producing a change in membrane potential of the postsynaptic cell. Their current may either increase or decrease the probability that action potentials will occur in that cell i.e. chemical synaptic signals can be either excitatory or inhibitory.
Fast chemical synapse:-
The transmitters used in fast transmission are small molecule packed small vesicles which are typically synthesized and packaged into Axon terminals. The most study of synaptic transmission has been done on fast chemical transmission at neurotransmitter junctions also called motor terminals, which joins the motor neurons and skeletal muscles fibre that they control. This transmission is fast because neurotransmitter directly binds to ion channels on postsynaptic membrane and change potential in the postsynaptic neuron. Neuromuscular Junction is used as our primary e.g. because first chemical signup transmission between neurons with the CNS closely resembles the transmission at the neuromuscular Junction although in many cases the transmitters are different
The Frog motor endplate includes structural specialities of the presynaptic terminals, postsynaptic membrane, associated Schwann cells.
At the terminal zone of presynaptic motor neurons, of motor and plate, numerous small branches( approx 2 micrometre in diameter) are present, each of which lies in a longitudinal dispersion along the surface of muscle fibre. The muscle membrane lining the depression is thrown into transverse fold called junction folds at intervals of 1 - 2 micrometre. Directly above each fold in the postsynaptic membrane is an active zone, in which many synaptic vesicles are clustered. The vesicle is released along to active zone by process of exocytosis.
There are thousands of vesicles, each about 50 nanometers in diameter, in a presynaptic terminal. Typically about 105 synaptic vesicles. The branches of nerve terminal innervate a single frog muscle fibre.
When vesicles fuse with the plasma membrane and release transmitter molecules into the synaptic cleft, the transmitter molecule reaches the postsynaptic membrane by diffusing down their concentration gradient. The cleft itself is filled with mucopolysaccharide that glue's together with the pre and postsynaptic membrane.
Acetylcholine is the neurotransmitter released at the neuromuscular junction. When it diffuses across the cleft, it binds to Ach - specific receptor molecule in the postsynaptic membrane causing ion channels to open that is selectivity for Sodium ion and potassium ion briefly. At the same time, the Ach is hydrolysed by the enzyme acetylcholinesterase (AchE) in the synaptic cleft. There is a race between diffusion of Ach molecules across the cleft and breakdown of each by acetylcholinesterase. Breakdown of neurotransmitter molecule in the synaptic deft limits the time during which the transmitter is active. In contrast to Ach, some neurotransmitters molecule are inactivated by being taken back up into presynaptic terminals, a process mediated by specialised transporter molecules.
In 1942 ”Stephen w kuffler” used extracellular electrodes to record electronic potential from a single fibre of the frog muscle. He discovered depolarisations intimately associate with the motor End Plate that took place in response to motor neurons action potentials. This proceeds the action potential generated in the muscle cells. The potential changes were highest in amplitude at the End Plate and gradually becomes lower with distance from the end plate. Given there apparent site of origin, kuffler names them End Plate Potentials (EPPs), a term still used specifically for postsynaptic potential in the muscle fibre. Kuffler correctly concludes that the arrival of the action potential in the presynaptic terminal could cause local depolarization of the postsynaptic membrane and thus initiate an action potential along the membrane of muscle fibre.
The development of Glass capillary microelectrode in the late 1940's made it possible to record potential produced in a much smaller tissue volume and hence to identify more precisely the source of end plate potentials. Like a neuron, muscle fibre has a resting potential across its plasma membrane. When a fibre is impaled by a microelectrode at a point several metres away from the motor end plate, the microelectrode records the resting potential and any 'all' or 'none' muscle action potential that pass through. Muscle action potential with every second after an action potential arrived in the terminal of the innervating motor axon, cause the muscle fibres to respond to each muscle action potential with twitch. Katz and others used pharmacological agents to explore the nature of nerve-muscle synapse.
for example - If the South American blow Dart-poison curare (D - tubocurarine) is applied to a frog nerve-muscle preparation and its concentration is increased, at some particular concentration there is a sudden, all or none failure of the muscle action potential, and the muscle fails to contract.
The action potential in the motor axon, however, remains unaffected. The poison, “curare” interfere directly with synaptic transmission at the neuromuscular junction by competing with Ach for binding at synaptic ion channels. A series of experiments, microelectrodes were inserted into muscle fibre at a variable distance from endplate region, and curare was added incrementally to the preparation.
The results are: -
a) When the microelectrode was inserted into the muscle fibre far from the end plate, the rising phase of the muscle action potential had a very steep slope.
b) On inserting the electrode close to the end plate the action potential arise slogan change in potential.
c) Adding curare to the saline bathing the muscle fibre modified the end plate potential.
At a low concentration of curare, some of the postsynaptic receptors were blocked and the synapses were weakened causing the end plate potential to rise more slowly. When the concentration of curare was high enough to depress the amplitude of the end plate potential below the threshold potential for an action potential in the muscle, there was an abrupt failure of muscle action potentials. Further increase in the concentration of curare reduced the initial slope amplitude of the end plate potential.
These results suggest that curare interfere with the synaptic transmission in its concentration and thus reduce the size of the end plate potential more and more as its concentration increased. If the recording electrode was now reinserted into the muscle fibre at a progressively greater distance from the motor end plate, the amplitude of endplate potential drop approximately exponentially with distance from the end plate
In contrast to the action potential, which propagates without attenuation because it is regenerating the end plate potential spread electrochemically and thus decrease with distance.
The chemical nature of neurotransmitters :
By mid-1960, only 3 compounds had been unequally identified as a neurotransmitter
3) Gamma aminobutyric acid (GABA)
In the process of identifying and characterizing these compounds, there were criteria established to distinguish neurotransmitter from other candidate molecules. These criteria are
1) When the substance is applied in the membrane of the postsynaptic cell, it must elicit precisely in the same physiological effect produced by presynaptic stimulation.
2) The substance must be released when the presynaptic neurons are active
3) The action of substance must be blocked by some agents that's blocked natural transmission of that synapse
Identifying the transmitter in the vertebrate CNS has been very difficult because very little transmitters are released at the most synapse (only about 104 molecules per synapse). A striking discovery that comes out of the search is that some neurotransmitters are used throughout the animal kingdom, providing an impressive example of evolutionary conservation of molecule identity. All transmitters ultimately modify the conduction of Ion channels in the postsynaptic cell, but the change in conductions is produced in different ways.
Some transmitters act directly on ion channel proteins to change conduction through the postsynaptic membrane thereby changing VM. This type of transmission is the fast or direct synaptic transmission.
Other transmissions through a biochemical pathway postsynaptic cell changing the state of membrane-associated or cytosolic second messengers that subsequently change the conduction through the ion channel. The shift in VM generated by this second type of transmitter take place more slowly because they depend on indirect modification of channels, so this type of transmission is called slow or indirect synaptic transmission.
Alternatively, neurotransmitters can be sorted into two groups based on their chemical structure. More than '40' neurotransmitters have been identified in the mammalian central nervous system.
One group consists of small molecules (table). The other group the neuropeptides consist of large molecules constructed of amino acids.
Neurotransmitters for fast or direct synaptic transmission: -
Among the low molecular weight neurotransmitters, only a few are known to fast neurotransmission. Acetylcholine, glutamate, Aspartic acid and ATP are frequently but not always associate with fast excitatory synaptic transmission. GABA and glycine mediate fast inhibitory transmission. All of these transmitters have been shown to open Ion channels in the membrane of the postsynaptic cell. Acetylcholine is most familiar with the established transmitter substance. Neurons that release acetylcholine which is said to be called cholinergic, are widely distributed through the Animal Kingdom.
Acetylcholine is neurotransmitter used by vertebrate motor neurons, the pre-ganglionic neurons of ANS, the postganglionic neurons of parasympathetic division of ANS and many neurons of vertebrate CNS.
Molecules that have chemical structural features in common with acetylcholine called structural analogous which can also act at cholinergic synapses. The structural analogue "carbachol" for example can active cholinergic synapsis. Molecules that mimics the action of neurotransmitters in this manner are said to be Agonist at the synapsis
Alternatively, structure analogue can block transmission by binding to the receptor site but not causing activation.
One more example is D- tubocurarine, the active agent curare, which competes with acetylcholine at receptor binding sites. Molecules that block the action of neurotransmitters in this manner are called antagonists. The calcium Ion concentration in the terminal must rise only in order to permit high fraction synaptic signalling, neurotransmitter molecule must occupy the synaptic cleft only. Transmission is terminated at cholinergic synapses when acetylcholine is hydrolysed to choline and acetate, that is done by acetylcholinesterase. Acetylcholinesterase is present in abundance at synaptic cleft near the surface of the postsynaptic membrane.
Some of the Acetate and choline diffuse away from cleft but choline that remains in the cleft is actively reabsorbed and recycled by condensation with acetyl coenzyme A to form New molecule of acetylcholine. Blocking the activity of acetylcholinesterase produce a dangerous effect.
At some synapses, the postsynaptic cell cannot be polarized and thus remain to activate. At many other synapses, the acetylcholine receptor molecule becomes inactivated in the process called synaptic desensitization. At the desensitized synapse, the postsynaptic membrane fails to respond to acetylcholine, even if it is present at high concentration.
In both cases, the formation of the nervous system and Muscular System is corrupted and death can follow. In vertebrates, death from this kind of poison is typically caused by paralysis of respiratory muscles. Glutamate is the most common transmitter at the excitatory synapse in the vertebrate central nervous system, and it is the transmitter at first excitatory junction in insect and crustaceans.
GABA is the transmitter at the inhibitory motor synapse in crustaceans and annelid muscles and an important inhibitory transmitter invertebrate central nervous system. Glycine is the most common inhibitory neurotransmitter in vertebrates spinal cord.
The neurotransmitter of slow indirect synaptic transmission:-
The biogenic Amines constitute an important class of neurotransmitters that access to second messengers to producers slow synaptic transmission.
Nor-epinephrine also was known as n-adrenaline is the primary transmitter released by postganglionic cells of the vertebrate synaptic nervous system. Neurons that use norepinephrine as the transmitter are called adrenergic neurons. At some synapses, norepinephrine is excitatory and maybe inhibitory. Its effect depends on the property of the postsynaptic cell. Nor-epinephrine is synthesized in synaptic terminals from the amino acid tyrosine, and it is inactivated by methylation within the synaptic cleft or by reuptake into Synaptics terminal, where some of it is repackaged into synaptic vessels for release and some are inverted by the enzyme monoamine oxidase.
Peptide molecules that are produced and released in the vertebrate central nervous system act as neurotransmitters, other act as modulators that influence synaptic transmission at the synapse from where they are released or at neighbouring synapses.
The first neuropeptide was discovered in 1913 by U.S. von Euler and John J. Gaddum while they were assaying for acetylcholine in the extract of rabbit brain and intestine.
Some example of neuropeptides is a ADH, substance 'p'.
Neuropeptides are typically synthesized from larger polypeptide called Pro peptides, each of which may contain the sequence for many biologically active peptides and proteins.
Peptides are more potent than small neurotransmitters due to 3-reasons:-
1) First, they bind to the receptor with great affinity than to other neurotransmitters
Their dissociation constant is about 10 -9 M, versus 10-5 for the typical neurotransmitter.
2) They act through the intracellular pathway that typically includes the Activation of enzymes that catalyse further reactions, producing significant amplification of the original signal.
A small amount of peptide transmitter can produce a large effect.
3) The mechanism that terminates the action of neuropeptides is slower than those for other neurotransmitters so they remain available for their receptor for a large time.
Electrical Synapsis :
Another type of synapses is electrical synapses. These synapses are formed where pre-synaptic and post-synaptic neurons are connected to each other by gap junction i.e. a pore made up of paired membrane channels, of pre-synaptic and post-synaptic attached to produce a continuous cytoplasmic link between pre-synaptic and post-synaptic neurons.
Gap Junctions :
Gap junctions are composed of paired channels of connexons which is formed by six transmembrane protein subunits called connexins. Each connexin is four-pass membrane-spanning protein subunit.
Variety of substances can pass through gap junctions along with ATP or several intracellular metabolites like second messengers, from one neuron to next neuron. Thus, ionic current can also flow passively through gap junction. Due to gap junctions, electrical transmission posses two exclusive features :
1) Transmission is extraordinary fast.
2) Transmission can be bidirectional.
Since transmission is very quick in electrical synapses, these have a general purpose to synchronize electrical activity among the population of neurons.