1. Introduction
Our attention will shift to mechanisms that coordinate the activities of the body’s organ systems. These activities are adjusted to meet changing situations and environmental conditions. This is termed as sensitivity, which is the ability to detect change and respond to it. Changes that are detected and lead to responses are called stimuli. You sit, stand or walk by controlling muscular activities; your body temperature remains stable on a cold winter day or in a warm kitchen because your rates of heat generation and heat loss are closely related.
In animals, 2 different but related systems coordinate closely to maintain homeostasis; the nervous system and the endocrine system. These systems share many characteristics, and they usually act in a complementary fashion.
The endocrine system adjusts the metabolic operations of other systems in response to changes in the availability of nutrients and the demand for energy. It also directs activities that continue for extended periods such as growth and maturation, sexual development, pregnancy and responses to chronic environmental stresses.
The nervous system provides swifter but generally briefer responses to stimuli by temporarily modifying the activities of other organ systems. Such modifications may appear in a matter of milliseconds, but the effects disappear soon after neural activity ceases.
There are 3 basic functions performed by the nervous system. First is to receive sensory input from internal and external environments. Next is to integrate and synchronize the inputs and finally, to give an effective response to the stimuli.
The nervous system is specialized in 3 things. Firstly is irritability. It is the ability to receive and respond to stimuli from the external and internal environments. Secondly is conduction. It is the ability to transmit signals to and from central integrating centres. Lastly is integration. It is the ability to analyze information from the environment in order to generate behavior appropriate to that information.
2. Cells of the nervous system
Nervous system is a network of billions or trillions of nerve cells linked together in a highly organized manner to form the rapid control system of the body. It is controlled by the brain and spinal chord which are also integrating centres for homeostasis, movement and many other body functions.
The nervous system is composed primarily of 2 cell types.
2.1 Neuroglia
They are called glial cells and they are supporting cells. They far outnumber neurons. Although there are about 100 billion neurons in the brain, there are about 10 – 15 times that many glia cells in the brain. They do not transmit electrical impulses. They function to aid in separating and protecting the neurons, provide a supporting framework for the neural tissue, act as phagocytes and help regulate the composition of interstitial fluid. Different types of neuroglia are found for the peripheral nervous system and the central nervous system.
2.2 Neurons
They are called nerve cells and they are the functional units of the nervous system. They are uniquely shaped with long appendages that extend outward from the cell body. These appendages, or processes, are usually classified as either dendrites or axons. Dendrites receive incoming signals and axons carry outgoing information.
2.2.1 Neuron Structure
2.2.1.1 Cell Body
It is also called soma or plural as somata. It contains the following sub-cellular organelles. The nucleus is relatively large and round with a prominent nucleolus. The perikaryon is the cytoplasm of the neurone that is surrounding the nucleus. The cytoskeleton is made up of neuro-filaments and neuro-tubules (equivalent to microfilaments and microtubules). Bundles of neuro-filaments called neuro-fibrils extend into the dendrites and axons, providing internal support for these slender processes. There are organelles that provide energy and synthesize organic materials especially the chemical neurotransmitters that are important in cell-to-cell communication. There are also numerous mitochondria, free and fixed ribosomes and rough ER, including Nissl bodies (clusters of rER and free ribosomes found in some areas of the perikaryon) that are darkly stained that account for the grey colour of areas containing neuron cell bodies.
2.2.1.2 Dendrites
These are slender, sensitive, highly-branched processes that extend out from the cell body and receive messages. It conducts nerve impulses towards the cell body.
2.2.1.3 Axon
This is a long cytoplasmic process capable of propagating an electrical impulse called an action potential. The axoplasm is the cytoplasm of the axon, containing neuro-fibrils, neuro-tubules, small vesicles, lysosomes, mitochondria and various enzymes. The axolemma surrounds the axoplasm and is a specialized portion of the cell membrane. The axon hillock is known as the trigger zone. It is a thickened area which is the point of attachment of the cell body to the base or initial segment of the axon in a multipolar neuron. Collaterals are the branchings of the main axon trunk. The telodendria are fine branchings of the collaterals bearing many tiny enlargements called synaptic knobs which end at synaptic terminals.
2.2.1.4 Synapse
Each synaptic terminal is part of a synapse, a specialized site where the neuron communicates with another cell. 2 cells meet at every synapse.
The pre-synaptic cell (usually a neuron) has the synaptic terminal and sends a message. The post-synaptic cell (usually a neuron or another cell type like the skeletal muscle cell) receives the message. A synapse between a neuron and a muscle cell is called a neuromuscular junction. A synapse between a neuron and a gland is called a neuro-glandular junction.
Communication between cells at a synapse most commonly involves the release of chemicals called neurotransmitters by the synaptic terminal. These chemicals, released by the pre-synaptic cell affects the activity of the post-synaptic cell.
2.2.2 Myelination of Axons
Schwann cells in the PNS support and insulate axons by creating myelin. These cells serve as supportive, nutritive and service facilities for neurons. Myelin is made up of multiple concentric layers of phospholipid membrane wrapped tightly round the axon. Where a Schwann cell covers an axon, the outer surface of the Schwann cell is called the neurilemma. A myelinating Schwann cell covers only one axon.
Between myelinated segments are small gaps called nodes of Ranvier, which serves as points along the neuron for generating a signal. The distance from one node to the next is called the internode. The thicker the diameter of the myelin sheath, the longer the internode. Thus, an axon that has a myelin sheath is called a myelinated axon. Signals jumping from node to node travel hundreds of times faster than signals traveling along the surface of the axon. This allows your brain to communicate with your toes in a few thousandths of a second.
2.2.3 Characteristics of Neurons
They have extreme longevity. Given good nutrition, they can live and function optimally for a lifetime (over 100 years).
They are unable to undergo mitosis (amitotic). Specialization of cells often leads to a loss of certain other cellular functions. As neurons assume their roles as communicating links of the nervous system, they lose their ability to undergo mitosis as evidently seen in the absence of centrioles in their cell bodies. We pay a dear price for this neuron feature because they are unable to reproduce themselves, they cannot be replaced if destroyed.
They have an exceptionally high metabolic rate. Neurons require continuous and abundant supplies of oxygen and glucose. They cannot survive for a few minutes without oxygen.
They are also easily excitable. They are able to respond to stimuli and can transmit signals.
2.2.4 Functional Organization of a typical Neuron
From top of cell body down to the synapses, there are the receptive segment, initial segment, the conductive segment and the transmissive segment.
2.2.5 Neuron Classification
A sensory neuron can be pseudounipolar or bipolar. They have long dendrites and a short axon. They conduct impulses along the afferent pathways to the CNS for interpretation. Unipolar neurons with processes are known as afferent fibres.
Internurons are multipolar. They conduct impulses within the CNS; may be one of a chain of CNS neurons or a single neuron connecting sensory and motor neurons.
Efferent Neurons are also multipolar. They have a long axon and short dendrites; they conduct impulses along the efferent pathways from the CNS to an effector (muscle or gland). Axons travelling away from the CNS are called efferent fibres.
2.3 Nerves
A nerve is a bundle of peripheral neuronal axons enclosed by a connective tissue covering and following the same pathway. It does not contain a complete nerve cell, only the axonal portions of many neurons. The individual fibres within a nerve generally do not have any direct influence on each other. They travel together for convenience, Blood vessels and lymphatic vessels are also found within the substance of a nerve. The anatomical term for bundles of nerve fibres and their myelin sheaths in the CNS is tracts. The term for those in the PNS is nerves.
A nerve fibre is the axon of a neurone together with the tissues associated with it (such as myelin sheath). The length and diameter of nerve fibres are very variable, even within the same organism. Nerves vary in size and are classified according to the direction in which they transmit impulses. Most nerves are mixed carrying both sensory and motor fibres and transmitting impulses both to and from the CNS. Purely sensory or motor nerves are rare.
3. Neurophysiology (the transmission of nerve impulses)
Neurons are specialized to respond to stimulation. They do this by generating several types of electrochemical impulses. These impulses are expressed as changes in the electrical potentials conducted along the cell membranes of the dendrites, cell body and axon or each neuron.
3.1 Electrical Properties of Neurons
Although a solution must have an equal number of positive and negative charges overall, these charges can be locally separated so that one region has more positive charges while another region has more negative charges. Because it takes work to separate charges, once they have been separated, they tend to move back towards each other. The tendency of oppositely charged ions to flow back towards each other is called a potential or voltage.
A membrane potential is a fundamental property of essentially all cells. It results from an excess of negatively charged species in one side of the cell membrane and an excess of positively charged ions on the other side. Cells at rest normally have an excess of negative charge inside and an excess of positive charge outside the cell.
3.1.1 Resting Membrane Potential
The plasma membrane of neurons at rest has an unequal distribution of ions and electrical charges between the 2 sides of the membrane. Outside of the membrane there are positive charges and inside of the membrane, there are negative charges. This charge difference is the resting potential (measured as millivolts, mV). The voltage is -70 to -100. (Negative because it is measured with respect to the inside of the membrane).
Resting potential results from the differences between positively charged ions (sodium ions and cations) and negative charged ions (anions like chloride ions and large macromolecules like proteins and RNA). An electrochemical gradient is a form of potential energy. Therefore, EC gradients for sodium and potassium ions are the primary factors affecting resting potentials of most cells including neurons
3.1.1.1 Establishment of the Resting Potential
The resting potential is established due to the following. There is the presence of potassium leak channels (passive diffusion) resulting in impermeable anions in the cytosol. There is distribution of ions across the membrane. There is the differential permeability of ions. Potassium ions are 50 to 100 times more permeable than sodium ions. Thus potassium ions leave the cytoplasm more rapidly than the Sodium ions entering.
3.1.1.2 Maintenance of the Resting Potential
Overtime, the ionic gradients will dissipate. But the potential is maintained or restored by active pumping by the sodium-potassium pump that transports ions against a concentration gradient. It pumps 2 potassium ions in and 3 sodium ions out of the cell using ATP through active transport. The more sodium that leaks into the neuron through the cell membrane, the more active the pump becomes, in order to restore the ionic concentrations that maintain the resting potential.
3.1.1.3 Changes in the Resting Membrane Potential
The resting potential is the transmembrane potential of an “undisturbed / unstimulated” cell. Yet cells are dynamic structures that continually modify their activities either in response to external stimuli or to perform specific functions. The transmembrane potential is equally dynamic, rising or falling in response to temporary changes in membrane permeability. Those changes result from the opening or closing of specific membrane channels.
3.1.1.3.1 Membrane / Ion Channels
3.1.1.3.1.1 Passive / Leak Channels
They are always open. However, their permeability can vary from moment to moment as the proteins that make up the channel change shape in response to local conditions. The Sodium and potassium leak channels are important in establishing the normal resting potential of the cell.
3.1.1.3.1.2 Active / Gated Channels
They open or close in response to specific stimuli. There are 3 classes of gated channels present.
3.1.1.3.1.2.1 Chemically Regulated Channels
They open or close when they bind specific chemicals like ACh (acetylcholine), a kind of neurotransmitter. The receptors that bind Ach at the neuromuscular junction are chemically regulated channels. These channels are most abundant on the dendrites and cell body of a neuron.
3.1.1.3.1.2.2 Voltage Regulated Channels
They are found on the excitable membranes of the neurons i.e. the axons. We are interested in 3 of such channels: the sodium, potassium and calcium channels. The potassium and calcium channels open or close in response to the changes in the resting potential. The opening of sodium channels is a key step in the generation of an action potential. They have 2 gates that function independently: an activation gate and an inactivation gate.
3.1.1.3.1.2.3 Mechanically Regulated Channels
They open and close in response to physical distortion; in the case of sensory receptors that respond to touch, pressure or vibration. This is not important in the nervous system.
3.1.2 Terminology
Polarization. Any time the value of the membrane potential is not 0mV, in either the positive or negative direction, the membrane is said to be in the state of polarization.
In depolarization, the membrane is less polarized than at resting potential. In essence, the membrane potential has decreased or moved closer to 0mV.
In repolarization, the membrane returns to resting potential after having been depolarized.
In hyperpolarization, the membrane is more polarized (more negative) than at resting potential. The potential has increased, or moved even further from 0mV.
The establishment of the resting potential and its dependence on ion permeability are properties of almost all cells and is not what makes electrically excitable cells unique. A non-excitable cell that has been temporarily and slightly depolarized will simply return to its original resting potential.
When an electrically excitable cell is depolarized to the same degree, it responds with graded potentials or an action potential (nerve impulses). Changes in membrane potential in excitable cells, neurons, are used as signals. The signals can come in 2 forms: graded potentials or action potentials.
3.1.3 Graded / Local Potentials (short distance signals in transmission of nerve impulses)
Graded potentials are changes in the resting potential that cannot spread far from the area surrounding the site of stimulation. They are depolarizations or hyperpolarizations that occur in the dendrites, cell body or less frequently, near the axon terminals. They are called graded potentials because of their size / amplitude is directly proportional to the strength of the triggering event and thus graded potentials reflect the strength of the stimulus that initiates them. A larger stimulus will open more channels and produce a larger change in permeability.
Graded potentials begin on the cell membrane at the point where ions enter from the extracellular fluid. For example, a neurotransmitter binds to the receptors of the dendrite, opening sodium channels. Sodium ions move into the neuron, bringing in electrical energy. The positive charge carried by the sodium ions spreads as a wave of depolarization through the cytoplasm of the cell body. The wave of depolarization that moves through the cell is called a local current.
The graded potential has 4 characteristics. The resting potential is more affected at the site of stimulation and the effect decreases with distance. The effect spreads passively due to local currents. They are either depolarization (opening or sodium ion channels) or hyperpolarization (opening of potassium ion channels) events. The stronger the stimulus, the greater the change in the resting potential and the larger the area affected.
Graded potentials travel through neurons until they die out of reach the region known as the trigger zone. In efferent neurons and interneurons, the trigger zone is the axon hillock and the very first part of the axon, a region known as the initial segment. In sensory neurons, the trigger zone is immediately adjacent to the receptor, where the dendrites join the axon.
The trigger zone is the integrating centre of the neuron. If graded potentials reaching the trigger zone depolarize the membrane to a minimum level known as the threshold voltage (i.e. suprathreshold) an action potential is initiated. If the depolarization does not reach the threshold (i.e. subthreshold), no action potential is initiated and the graded potential simply dies out.
The strength of the initial depolarization in a graded potential is determined by how much charge enters the cell. If more sodium ion channels open, more sodium ions enter and the graded potential has higher initial amplitude. The stronger the initial amplitude, the farther the graded potential can spread through the neuron before it dies out.
3.1.4 Action Potentials (Long distance signals in transmission of nerve impulses)
Action potentials are propagated changes in the transmembrane potential that, once initiated, affect an entire excitable membrane. In a motor neuron, an action potential is generated at the axon hillock of the axon, then propagated / conducted along the length of the axon and ultimately reaching the synaptic terminals.
They are also known as spikes and differ from graded potentials in several ways. All action potentials are brief and they do not diminish in strength as they travel through the neuron away from the stimulus point. This is known as non-decremental conduction.
3.1.4.1 All – or – none Principle
The stimulus that initiates an action potential is a depolarization large enough to open voltage-regulated sodium channels. That opening occurs at a potential called the threshold. A stimulus that shifts the resting potential from -70mV to -60mV will not produce an action potential, only a graded depolarization. Recordings of action potentials show them to be identical depolarizations of about 100mV amplitude. The strength of the graded potential that initiates an action potential has no influence on its amplitude.
Action potentials exhibit the all-or-none principle as they either occur as a maximal depolarization (if the stimulus reaches a threshold) or do not occur at all (if the stimulus is below the threshold). This means that the amplitude (height) of the action potential does not vary with the strength of the stimulus.
3.1.4.2 Generation of an Action Potential
The graph of an action potential can be divided into 3 phases: the rising phase, the falling phase and the after-hyperpolarization phase. Before and after the action potential, the neuron is at resting potential of -70mV.
3.1.4.2.1 Rising Phase of the Action Potential (Depolarization)
At rest, the outside of the membrane is more positive than the inside (resting potential).
Action potential begins when a graded potential reaching the axon hillock depolarizes the membrane to a threshold (-55mV). Upon stimulation (if stimulus is above the threshold), voltage regulated sodium ion gates open, increasing the membrane permeability to sodium ions. This causes a sudden influx of positive sodium ions along a concentration gradient making the inside of the cell more positive than the outside. This is the upstroke of the action potential and the sodium-potassium pump is inactivated.
The opening of gates results in local currents that move to adjacent areas causing more gates to open (this is an example of positive feedback response) that would cause even more gates to open. This results in dramatic changes in polarity towards the positive (depolarization). This is known as an overshoot or the spike potential. The total depolarization associated with the action potential has been from -70mV to +30mV.
As long as the sodium ion permeability remains high, the membrane potential moves toward sodium ion equilibrium (i.e. inside and outside of the membrane, the sodium ion potential is almost the same). Here, the sodium ion channels will close in the axon. Sodium permeability decreases dramatically, and the action potential peaks at +30mV.
3.1.4.2.2 Falling Phase of the Action Potential
This is due primarily to an increase in potassium ion permeability. Voltage-gated potassium ion channels, like the sodium ion channels, open in response to the depolarization. But the potassium ion channels are slower to open and the peak of potassium ion permeability occurs later than the peak for sodium ion permeability. By the time the potassium ion channels are open, the membrane potential of the cell has reached +30mVV because of the sodium ion influx. When the sodium ion channels close, the electrochemical gradient for potassium ion favours the movement of potassium ions out of the cell.
As potassium ions move out of the cytoplasm, the membrane potential becomes more negative, creating the falling phase and sending the cell towards it resting potential. This restores the resting potential net charges (i.e. the inside is once again negative and the outside positive). The membrane is now said to have repolarized.
The potassium channels close slowly, so instead of repolarizing to exactly -70mV, the cell hyperpolarizes, approaching -90mV. This additional loss of potassium creates an after-hyperpolarization (a.k.a. undershoot).
Once the voltage-gated potassium ion channels close, potassium ion leakage into the cell exceeds movement out, bringing the membrane potential back to its normal resting value of -70mV.
3.1.4.3 How the voltage-regulated sodium ion channels work during the action potential
One question that puzzled scientists for many years was how the sodium channels could close when the cell was depolarized, because depolarization was the stimulus for sodium ion channels to open. After many years of studying, it was recently discovered that the sodium channels has 2 gates to regulate ion movement rather than a simple gate. These 2 gates, known as activation and inactivation gates, flip-flop back and forth to open and shut the sodium ion channel.
3.1.4.4 Action Potential and Refractory Periods
The double gating of the sodium ion channel plays a major role in the phenomenon known as the refractory period.
3.1.4.4.1 Absolute Refractory Period
The “stubbornness” if the neuron refers to the fact that once an action potential has begun, for about 1msec, a second action potential cannot be triggered no matter how large the stimulus. This is known as the absolute refractory period. It ensures that a second action potential will not occur before the first has finished. Action potentials cannot overlap because of their refractory periods.
3.1.4.4.2 Relative Refractory Period
After the sodium ion channel gates have reset to their original positions, but before the membrane is restored to its resting potential, a higher-than-normal graded potential can start another action potential. During this time, the neuron is said to be in its relative refractory period.
A threshold-level depolarization during this period will open those sodium ion channels that have returned to their resting position. However, sodium ion entry through these channels is offset by potassium ion loss through the still open potassium ion channels. The opposing flow of charge balances out and the membrane potential does not reach a threshold. For that reason, a stronger-than-normal depolarization graded potential is needed to bring the cell up to the threshold for an action potential.
3.1.4.4.3 Significance of the Refractory Periods
The refractory period is a key characteristic that distinguishes action potentials from graded potentials. If 2 stimuli reach the dendrites of a neuron within a short time, the successive graded potentials can be added to each other. But if 2 suprathreshold graded potentials reach the action potential trigger zone within the absolute refractory period, the second stimulus will be ignored because the sodium ion channels are inactivated and are incapable of being stimulated again so soon.
Refractory periods limit the rate at which signals can be transmitted down a neuron. The absolute refractory period also ensures one way traffic of an action potential from the cell body to an axon terminal by preventing backward conduction of the action potential.
3.1.5 Stimulus Intensity is coded by frequency of Action Potentials
One distinguishing characteristic of action potentials is that every action potential in a give neuron will be identical to every other action potential in that neuron. But if this is so, then how does the neuron transmit information about the strength and duration of the stimulus that started the action potential? The answer lies not in the amplitude of the action potential, but in the frequency of action potential propagation.
A stimulus in the form of a graded potential reaching the trigger zone does not usually trigger a single action potential. Instead, even a minimal graded potential that is above the threshold will trigger a burst of action potentials.
If the graded potential increases in strength, the frequency of action potentials fired increases. The amount of neurotransmitter released at the axon terminal is directly related to the total number of action potentials that arrive at the terminal per unit time. An increase in signal strength increases the neurotransmitter output. This will change the magnitude of the graded potential in the post-synaptic cell.
3.1.6 Propagation / Conduction of Action Potentials
The movement of an action potential through the axon at high speeds is called propagation or conduction. It represents the flow of electrical energy from one part of the cell to another in a process that ensures that any energy lost to friction or leakage out of the cell is immediately replenished. Thus, an action potential does not lose strength over distance as a graded potential does.
3.1.6.1 Continuous Propagation
Once a graded potential reaches threshold in the trigger zone, voltage-regulated sodium ion channels open and the cell depolarizes. The positive current from the sodium ions’ entry spreads through the cytoplasm in all directions (just as the depolarization of a graded potential spreads through the cell by local current flow).
The axolemma is lined by the same type of voltage-regulated sodium ion channels found in the membrane of the trigger zone. Positive charges from the depolarization of the trigger zone spread into adjacent sections of the membrane (attracted by the negative charge of the resting membrane potential). When the wave of depolarization reaches the voltage-regulated sodium ion channels adjacent to the trigger zone, they open, allowing the sodium ions into the cell. The membrane in the next segment of the axon is depolarized, and the positive feedback loop of depolarization begins.
The continuous entry of sodium ions means that the strength of the signal does not diminish as the action potential propagates itself. Although positive charge from distal, depolarizing segments of the membrane may flow back p into these segments by local current flow, the depolarization has no effect. This part of the axon is in absolute refractory period, with its voltage-regulated sodium ion channels inactivated, and the action potential cannot move backwards.
3.1.6.2 Saltatory Propagation
In a myelinated axon, the axolemma is wrapped in a myelin sheath that is complete except at the nodes. Continuous propagation cannot occur along a myelinated axon because myelin increases resistance to the flow of ions across the membrane. Ions can readily cross the cell membrane only at the nodes. As a result, only the nodes can respond to a depolarizing stimulus.
When an action potential appears at the initial segment of a myelinated axon, the local current skips the internodes and depolarizes the closest node to threshold. Because the nodes may be 1 – 2 mm apart in a large myelinated axon, the action potential “jumps” from node to node rather than moving along the axons in a series of tiny steps. This process is called saltatory propagation.
Saltatory propagation in the CNS and PNS carries nerve impulses along the axon much more rapidly than does continuous propagation. It also uses proportionately less energy, because less surface area is involved and fewer sodium ions need to be pumped out of the cytoplasm.
3.1.6.3 Axon Diameter and Propagation Speed
The larger the diameter of the axon, the faster the rate of conduction. This is due to a larger cross-sectional and membrane area that together provide lower resistance.
The presence of a myelin sheath increases the rate of impulse propagation. They act as an insulator to prevent leakage of charges. Current will pass through the membrane only at the nodes of Ranvier thus the impulses are forced to jump from one node to the other (about 1 – 2 mm) increasing the rate of transmission. This is known as saltatory conduction. In vertebrates, most of the neurons have myelinated axons.
3.1.7 Synaptic Transmission (cell-to-cell communication in the nervous system)
Synapses are unique junctions that control communication between a neuron and another cell. Synapses are found between 2 neurons, between sensory receptors and sensory neurons, between motor neurons and muscle cells they control, an between neurons and gland cells.
Here, we focus on synapses between neurons, which usually conduct signals form an axon’s synaptic terminals to dendrites or cell bodies of the next cell in a neural pathway. The transmitting cell is called the per-synaptic cell and the receiving cell is called the post-synaptic cell. There are 2 types of synapses. We will just learn the chemical synapses.
3.1.7.1 Chemical Synapses
At a chemical synapse, an arriving action potential may or may not release enough neurotransmitter to bring the post-synaptic neuron to threshold. In addition, the post-synaptic cell at a chemical synapse is not a slave to the pre-synaptic neuron; its activity can be adjusted by a variety of factors. Communication across a chemical synapse can normally occur in only one direction from the pre-synaptic membrane to the post-synaptic membrane.
Excitatory neurotransmitters causes depolarization and promote action potential propagation. Inhibitory neurotransmitters causes hyperpolarization and suppress the action potential generation.
3.1.7.1.1 Cholinergic Synapses
We shall focus on chemical synapses that release the neurotransmitter acetylcholine (ACh). These are known as cholinergic synapses. The neuromuscular junction is a cholinergic synapse. At a cholinergic synapse between 2 neurons, the pre-synaptic and post-synaptic membranes are separated by a synaptic cleft that averages 20nm in width, Most of the Ach in the synaptic knob is packaged in synaptic vesicles, each containing several thousand molecules of neurotransmitter. A single synaptic knob may contain a million of such vesicles.
Step 1 is the arrival of an action potential and depolarization of the synaptic knob. The normal stimulus for neurotransmitter release is the depolarization of the synaptic knob by the arrival of an action potential.
Step 2 is the entry of extracellular calcium ions into the synaptic knob, triggering the exocytosis of ACh. The depolarization of the synaptic knob opens voltage-regulated calcium channels. Calcium ions rush into the synaptic knob. Their arrival triggers exocytosis and the release of ACh into the synaptic cleft. The release of ACh stops very soon, because the calcium ions that triggered exocytosis are rapidly removed from the cytoplasm by active transport mechanisms. These mechanisms either pump calcium ions out of the cell or transfer them into the mitochondria vesicles or the ER.
Step3 is the binding of ACh and the depolarization of the post-synaptic membrane. The ACh released through exocytosis diffuses across the synaptic cleft toward the receptors on the post-synaptic membrane that are chemically regulated ion channels. The primary response is an increased permeability to sodium ions, producing a depolarization that lasts about 20msec. This depolarization is a graded potential: the more ACh released at the pre-synaptic membrane, the larger the depolarization. If the depolarization brings an adjacent area of excitable membrane to threshold, an action potential will appear in the post-synaptic neuron.
Although some neurons can transmit impulses at rates that approach 100mm / msec, neural transmission across a chemical synapse is comparatively slower and is known as the synaptic delay. It is due to time taken for the vesicles containing the neurotransmitter to fuse with the pre-synaptic membrane, release of the neurotransmitter into the synaptic cleft, diffusion of the neurotransmitter across the synaptic cleft and for the neurotransmitter to bind with the receptor molecules in the post-synaptic membrane.
Step 4 is the removal of ACh by acetylcholinesterase (ACHE) The effects on the post-synaptic membrane are temporary because the synaptic cleft and the post synaptic membrane contains ACHE. More than half of the ACh released at the pre-synaptic membrane is broken down before it reaches the receptors of the post-synaptic membrane. ACh molecules that succeed in binding to the receptor sites are generally broken down within 20msec on their arrival. The enzyme ACHE breaks down ACh into acetate and choline. The choline us actively absorbed by the synaptic knob and is used to synthesize more ACh using acetate provided by coenzyme A. Acetate diffusing away from the synapse can be absorbed and metabolized by the post-synaptic cells or by other cells and tissues.
3.1.8 Information Processing – Postsynaptic Potentials
A single neuron may receive information from numerous neighbouring neurons via thousands of synapses, some of them excitatory and others, from different neurons, inhibitory. The net result is the generation of post-synaptic potentials that can be a depolarization or a hyperpolarization.
3.1.8.1 Post-synaptic Potentials
They are graded potentials that develop in the post-synaptic membrane in response to a neurotransmitter. They vary in magnitude with the number of neurotransmitter molecules binding to receptors on the post-synaptic membrane.
3.1.8.1.1 Excitatory Post-Synaptic Potentials (EPSPs)
It is a graded depolarization caused by the arrival of a neurotransmitter at the post-synaptic membrane. Binding of neurotransmitters increase permeability of the post-synaptic membrane to sodium ions by opening the sodium ion gates to bring about depolarization. Because an EPSP makes the post-synaptic membrane more excitable, it does increase the chance of generating an action potential.
3.1.8.1.2 Inhibitory Post-synaptic Potentials (IPSPs)
It is a graded hyperpolarization of the post-synaptic membrane. The binding of neurotransmitters results in the opening of potassium ion and chloride ion gates. The entry of chloride ions and the exit of potassium ions make the inside of the cell more negative. Inhibition occurs as hyperpolarization of the membrane and t makes the inside of the post-synaptic membrane more negative with respect to the outside. Thus, making it more difficult to generate an action potential.
3.1.8.2 Summations
A single EPSP at one synapse, even one close to the axon hillock, is not usually enough to trigger an action potential. However, several synaptic terminals acting simultaneously on the same post-synaptic cell, or a smaller number of synaptic terminals discharging neurotransmitters repeatedly in a rapid fire succession, can have a cumulative effect on the membrane potential at the axon hillock.
This additive effect of the post-synaptic potentials is called summation.
For temporal summation, the chemical transmissions from one or more synaptic terminals occur so close together in time that each post-synaptic potential affects the membrane before the voltage has returned to the resting potential after the previous summation.
For spatial summation, several different synaptic terminals, usually belonging to different pre-synaptic neurons, stimulate a post-synaptic cell at the same time and have an additive effect to the membrane potential.
