Introduction:
All multicellular organisms have a nervous system, which may be defined as assemblages of cells specialized by their shape and function to act as the major coordinating organ of the body. Nervous tissue underlies the ability to sense the environment, to move and react to stimuli, and to generate and control all behavior of the organism. Compared to vertebrate nervous systems, invertebrate systems are somewhat simpler and can be more easily analyzed. Invertebrate nerve cells tend to be much larger and fewer in number than those of vertebrates. They are also easily accessible and less complexly organized; and they are hardy and amenable to revealing experimental manipulations. However, the rules governing the structure, chemistry, organization, and function of nervous tissue have been strongly conserved phylogenetically. Therefore, although humans and the higher vertebrates have unique behavioral and intellectual capabilities, the underlying physical-chemical principles of nerve cell activity and the strategies for organizing higher nervous systems are already present in the lower forms. Thus neuroscientists have taken advantage of the simpler nervous systems of invertebrates to acquire further understanding of those processes by which all brains function.
Nerve:
A nerve is an enclosed, cable-like bundle of peripheral axons (the long, slender projections of neurons). A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system. In the central nervous system, the analogous structures are known as tracts. Neurons are sometimes called nerve cells, though this term is technically inaccurate since many neurons do not form nerves, and nerves also include non-neuronal Schwann cells that coat the axons in myelin. Nerves are categorized into three groups based on the direction that signals are conducted: Nerves can be categorized into two groups based on where they connect to the central nervous system: Within the endoneurium, the individual nerve fibers are surrounded by a low protein liquid called endoneurial fluid. The endoneurium has properties analogous to the blood-brain barrier, in that it prevents certain molecules
The Nerve Message :
The plasma membrane of neurons, like all other cells, has an unequal distribution of ions and electrical charges between the two sides of the membrane. The outside of the membrane has a positive charge, inside has a negative charge. This charge difference is a resting potential and is measured in millivolts. Passage of ions across the cell membrane passes the electrical charge along the cell. The voltage potential is -65mV (millivolts) of a cell at rest (resting potential). Resting potential results from differences between sodium and potassium positively charged ions and negatively charged ions in the cytoplasm. Sodium ions are more concentrated outside the membrane, while potassium ions are more concentrated inside the membrane. This imbalance is maintained by the active transport of ions to reset the membrane known as the sodium potassium pump. The sodium-potassium pump maintains this unequal concentration by actively transporting ions against their concentration gradients.
Fig: Transmission of an action potential..
Changed polarity of the membrane, the action potential, results in propagation of the nerve impulse along the membrane. An action potential is a temporary reversal of the electrical potential along the membrane for a few milliseconds. Sodium gates and potassium gates open in the membrane to allow their respective ions to cross. Sodium and potassium ions reverse positions by passing through membrane protein channel gates that can be opened or closed to control ion passage. Sodium crosses first. At the height of the membrane potential reversal, potassium channels open to allow potassium ions to pass to the outside of the membrane. Potassium crosses second, resulting in changed ionic distributions, which must be reset by the continuously running sodium-potassium pump. Eventually enough potassium ions pass to the outside to restore the membrane charges to those of the original resting potential.The cell begins then to pump the ions back to their original sides of the membrane.
The action potential begins at one spot on the membrane, but spreads to adjacent areas of the membrane, propagating the message along the length of the cell membrane. After passage of the action potential, there is a brief period, the refractory period, during which the membrane cannot be stimulated. This prevents the message from being transmitted backward along the membrane
Steps in an Action Potential
- At rest the outside of the membrane is more positive than the inside.
- Sodium moves inside the cell causing an action potential, the influx of positive sodium ions makes the inside of the membrane more positive than the outside.
- Potassium ions flow out of the cell, restoring the resting potential net charges.
- Sodium ions are pumped out of the cell and potassium ions are pumped into the cell, restoring the original distribution of ions.
Synapses :
The junction between a nerve cell and another cell is called a synapse. Messages travel within the neuron as an electrical action potential. The space between two cells is known as the synaptic cleft. To cross the synaptic cleft requires the actions of neurotransmitters. Neurotransmitters are stored in small synaptic vessicles clustered at the tip of the axon.
Fig: Synapes 
Neuron:
The neuron is the functional unit of the nervous system. Humans have about 100 billion neurons in their brain alone! While variable in size and shape, all neurons have three parts. Dendrites receive information from another cell and transmit the message to the cell body. The cell body contains the nucleus, mitochondria and other organelles typical of eukaryotic cells. The axon conducts messages away from the cell body.
What is Neuromuscular Transmission (NMT)?
Neuromuscular Transmission (NMT) is the transfer of an impulse between a nerve and a muscle in the neuromuscular junction. NMT can be blocked by neuromuscular blocking agents -drugs which cause transient muscle paralysis and prevent the patient from moving and breathing spontaneously.
Muscle relaxation is used during general anesthesia to enable endotracheal intubation and to provide the surgeon with optimal working conditions. In critical care muscle relaxation is used during mechanical ventilation to minimize the patient ’s work of breathing and to improve oxygenation.
A) Overview of Neuromuscular Transmission
An action potential originating at the axon hillock of a motor neuron is conducted to the nerve terminal
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Nerve terminal is depolarized opening Ca channels
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Vesicles fuse with nerve terminal membrane and release Acetylcholine (Ach)
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ACh binds to receptors on the muscle end-plate → Depolarization of the muscle membrane
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Threshold of Voltage-sensitive Na channels in muscle membrane is reached, and muscle AP fires
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AP spreads over surface of muscle and muscle contracts
B) Structure of the Neuromuscular Junction
1) At the neuromuscular junction an alpha motor neuron loses its myelin sheath and forms numerous nerve terminal branches. Each of these branches ends in a terminal bulb called a “bouton.”
2) The terminal boutons remain close and form synaptic contacts on a specialized area of muscle cell membrane called the “end-plate.”
3) Between the “pre-synaptic” nerve terminal and the “post-synaptic” muscle end-plate is 20 nm cleft containing a basal lamina sheath consisting of collagen and extracellular matrix proteins. An enzyme “acetyl cholinesterase” is also present in the synaptic cleft. This enzyme hydrolyzes Acetylcholine into choline plus acetate.
4) Structures in the Nerve Terminal
a) All nerve terminals in chemical synapses contain: vesicles with transmitter, mitochondria and an “active zone” where vesicles bind and release their contents into the synaptic cleft
b) Nerve terminals also contain Ca channels near the active zones. Ca facilitates the fusion of vesicles with the nerve terminal membrane. In the absence of Ca, neuromuscular transmission cannot occur.
5) Structures in the Synaptic Cleft
a) The 20 nm cleft is filled with collagen and extracellular matrix proteins. Acetylcholine esterase (AChE) is also located in the cleft attached to the collagen.
b) During development molecules are expressed that enable the growing nerve terminal to form a synapse on the correct target.
c) When ACh is released from nerve terminal vesicles, the transmitter diffuses across the cleft and binds to ACh receptors on the muscle end-plate. However, because the enzyme AChE is so effective, most of the Ach is hydrolyzed before it reaches the receptors.
6)Structures at the Muscle End-plate
a)The muscle end-plate is thrown into a highly convoluted series of folds that are characteristic of mature neuromuscular junctions.
b)ACh receptors are localized in clusters at the crests of the folds, strategically located across from the vesicle binding/release sites.
c)When ACh binds to the receptors, the end-plate membrane is “punctured” for cations, allowing Na+ and K+ to diffuse down their chemical gradients. Thus Na moves in and K moves out leading to a depolarization of the end-plate membrane.
d)Voltage-sensitive Na channels are located at the bottoms of the folds and in all the rest of the muscle membrane. If the end-plate depolarization is sufficient to reach threshold, a muscle AP will fire, and the muscle will contract.
C) Steps in Neuromuscular Transmission – Pre-synaptic
1)Nerve Terminal Action Potential Opens Ca Channels
a)Voltage-sensitive Ca channels are especially concentrated in nerve terminal endings near vesicle release sites. These Ca channels have activation and inactivation gates, but are slow to open and close.
b)Because they are slow, the Ca channels open during the falling phase of the nerve terminal AP. The Ca channels are open long enough to allow a rise in intracellular Ca of 1000 times normal (~ 10-4 M, whereas normal is ~ 10-7 M).
c)The rise in Ca++ near vesicle binding sites allows fusion of vesicle membranes with the nerve terminal membrane.
d)Vesicle Docking – A fusion pore develops beneath a “docked” vesicle. A channel forms through the fusion pore allowing some ACh to be released. In the final state an “omega figure” is formed, and the ACh is released from the vesicle. The vesicle membrane becomes incorporated into the nerve terminal membrane.
e)Vesicle Recycling
1)Slow to Moderate rates of stimulation – “Kiss and Run Docking.”
2)Fast Stimulation – Fusion and Recycling of Membrane.
a)Vesicles fuse with nerve terminal membrane, form Omega figures, and combine with the membrane
b)Clathrin forms around an invaginated region of membrane. Clathrin proteins form a basket around a pinched off piece of nerve terminal membrane, and transport it to the endosome.
a) New vesicles are formed from the endosome and move to the terminal along cytoskeletal elements.
b) Newly formed vesicles are refilled with ACh by the reaction of choline + acetate catalyzed by the enzyme Acetylcholine transferase.
D) Steps in Neuromuscular Transmission – Post Synaptic
1)Acetylcholine is released into the synaptic cleft directly opposite the ACh Receptors. These are “nicotinic” acetylcholine receptors because they have a high affinity for nicotine as apposed to “muscarine” typical of the autonomic nervous system.
2)Most acetylcholine never reaches the Ach receptors. That is because the synaptic cleft is filled with the enzyme acetylcholine esterase (AChE) that hydrolyzes most of the Ach. The released Ach must pass through this enzyme “gauntlet.”
Ach + Ach esterase → acetate + choline
3)The choline is taken back into the nerve terminal where it is combined with Acetyl CoA in the presence of the enzyme CAT (choline acetyl transferase). The Ach is then repackaged in vesicles for future release.
Choline + AcetylCoA + CAT → Acetylcholine
4)When ACh binds to the receptors, it opens a special channel that “chemically punctures” the end-plate membrane to both Na+ and K+.
5)The opening of the Ach-controlled channel leads to a depolarization of the end-plate region called the “end-plate potential.”
6) The EPP is recorded by placing a microelectrode into the muscle cell near the end-plate.
a) A typical EPP is about 50-60 mV in amplitude. It is usually not seen because as the muscle membrane is depolarized to threshold, voltage-sensitive Na channels on the muscle membrane are activated leading to an all-or-none Action Potential.
b) But it is possible to reduce the amplitude of the EPP to below threshold using curare, a South American alkaloid used by natives for arrow poison.
c) Curare binds to the ACh receptor, and competes with ACh. Although curare binds to Ach receptors, it cannot open the receptor channel, and thus cannot depolarize the end-plate membrane. Therefore, the ACh released from vesicles produces less depolarization of the end-plate membrane.
d) Curare was used in the past as an agent for muscle paralysis to permit surgery especially around joints. It has since been replaced by faster acting and more controllable agents.
7) Characterization of the Acetylcholine Receptor
1) Karlin and Changeux are primarily responsible for our understanding of the structure and function of the nicotinic ACh receptor (AChR).
2) The Nicotinic AChR consists of five subunits: two α’s, β, γ and δ. For maximum effect two ACh molecules must bind to the receptor, one at each alpha site.
3) Once ACh is bound the channel opens, and Na+ flow into the cell down its electrical and chemical gradient; K+ flows out down its chemical gradient. Bernard Katz termed this “a chemical puncture” of the end-plate membrane.
* How does the EPP lead to a Muscle Action Potential?
a) The end-plate is usually found in the center of a muscle fiber.
b) Recall the discussion about conduction of a nerve action potential. Depolarization of the end-plate membrane causes a discharge of the capacitance in the surrounding muscle membrane. Eventually enough charge is drawn off of this capacitance to bring the muscle membrane to – 60 mV, the threshold for voltage sensitive Na-chann.
c) The voltage-sensitive Na channels are located in the depths of the end-plate folds and in the muscle membrane away from the end-plate.
d) As these voltage-gated Na channels reach threshold, the activation gates open and (just as in nerve axons) a regenerative muscle action potential occurs.
e) The AP is conducted from the center of the muscle fiber outward.This eventually leads to muscle contraction (discussed later ).
Disorders of Neuromuscular Transmission
Disorders of neuromuscular transmission affect the neuromuscular junction. They may involve
- Postsynaptic receptors (eg, in myasthenia gravis)
- Presynaptic release of acetylcholine (eg, in botulism)
- Breakdown of acetylcholine within the synapse (eg, due to drugs or neurotoxic chemicals)
Common features of these disorders include fluctuating fatigue and muscle weakness with no sensory deficits.
Eaton-Lambert syndrome: This disorder is due to impaired acetylcholine release from presynaptic nerve.
Botulism: Also due to impaired release of acetylcholine from presynaptic nerve terminals, botulism develops when toxin produced by Clostridium botulinum spores irreversibly binds to the terminal cholinergic nerve endings. The result is severe weakness, sometimes with respiratory compromise. Other systemic symptoms may include mydriasis, dry mouth, constipation, urinary retention, and tachycardia due to unopposed sympathetic nervous system activity (anticholinergic syndrome). These systemic findings are absent in myasthenia gravis..
Drugs or toxic chemicals: Cholinergic drugs, organophosphate insecticides, and most nerve gases block neuromuscular transmission by excessive acetylcholine action that depolarizes postsynaptic receptors. Miosis, bronchorrhea, and myasthenic-like weakness (cholinergic syndrome) result.
Aminoglycoside and polypeptide antibiotics decrease presynaptic acetylcholine release and sensitivity of the postsynaptic membrane to acetylcholine. At high serum levels, these antibiotics may increase neuromuscular block in patients with latent myasthenia gravis.
Other Disorder:
1.Myasthenia gravis
2.Neuromyotonia
3.Lambert-Eaton myasthenic symptoms
Treatment :
1. Myasthenia gravis
· Acetylcholine esterase inhibitors
· Short-term plasma exchange treatment
· Intravenous immunoglobulin (IvIg)
· Thymectomy
· Oral corticosteroids (with a bisphosphonate and antacid)
· Azathioprine
· Other immunosuppressants
2. Lambert-Eaton myasthenic syndrome
· 3,4-diaminopyridine with or without pyridostigmine
· IvIg
· Treatment of the underlying tumor
· Immunosupressive treatment
3. Neuromyotonia
· Antiepileptic drugs
· Treatment of the underlying tumor
· Immunomodulatory therapiedrome
Conclusion :
To identify and investigate any dysfunction of neuromuscular transmission in episodic cluster headache. Abnormal neuromuscular transmission has been shown in migraine with aura and in migraine without aura by using single fiber electromyography. Especially for migraine with aura, a genetic cause has been postulated. Episodic cluster headache is a primary headache disorder in which genetic factors may, at times, play a strong role. Methods.-Single fiber electromyography during voluntary contraction of the extensor digitorum communis muscle, nerve conduction studies of upper and lower extremities.
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