Lec 2 Doha (1) PDF - Neurotransmission & Action Potential Propagation

Pathophysiology of diseases affecting neurotransmission and action potential propagation Dr. Doha Al- Afifi Objectives  Understand the definition of synapse.  Understand the structure of synapse.  Understand the process of synaptic transmission.  Different pathogenesis of diseases related to sy...

Pathophysiology of diseases affecting neurotransmission and action potential propagation Dr. Doha Al- Afifi Objectives  Understand the definition of synapse.  Understand the structure of synapse.  Understand the process of synaptic transmission.  Different pathogenesis of diseases related to synaptic transmission. Components of Neurons Atypical neuron has four main components: 1) Soma 2) Dendrites 3)Axon 4) presynaptic terminals 1. Cell body :  The soma synthesizes a large quantity and variety of proteins used as neurotransmitters 2.Dendrites:  Dendrites, branch-like extensions that serve as the main input sites for the cell, project from the soma.  They are specialized to receive information from other cells. 3.Axon:  Most neuron has a single axon that arise from a specialized region within the cell called Axon hillock.  The axon hillock is the last site in the soma where membrane potentials propagated from synaptic inputs are summated before being transmitted to the axon. The axon hillock is the site of action potential initiation (trigger zone).  The axon is the output unit of the cell, specialized to send information to other neurons, muscle cells, or glands.  Axons vary in length. The shortest axons are less than 1 mm in length,' whereas axons that transmit motor information from the spinal cord to the foot may be up to 1 meter long. Axonal Transport Axonal transport: The cellular mechanism that transports substances along an axon. Axoplasmic transport occurs in two directions: anterograde and retrograde. Anterograde transport moves neurotransmitters and other substances from the soma down the axon toward the presynaptic terminal. Retrograde transport moves substances from synapse back to the soma.. The effect of myelination  Myelin sheath is present around some axons within the Peripheral nervous system (PNS), where it is produced by Schwann cell.  And within the Central nervous system (CNS) , where it is produced by Oligodendrocytes (a type of glial cell).  The smallest axons are unmyelinated. The effect of myelination  Myelin sheath has a profound effects on conduction propagation of action potentials along the axons.  Myelin functions as an insulator. In general, myelination serves to increase the speed of impulse conduction along the axon.  The myelin sheath is divided into segments about 1 mm long by small gaps (1 μm long) where myelin is absent; these are the (nodes of Ranvier). Axons Axons may be myelinated or unmyelinated. Myelinated axons are insulated by a sheath of myelin that starts near the cell body and stops just before the axon terminates. Myelin is a multilayered phospholipid located within axonal supporting cells. The velocity of propagation of an action potential is dependent on axonal diameter and myelination. The myelin sheath increases the conduction velocity of the nerve impulse along the axon. The thicker the myelin sheath, the faster the conduction velocity. 11 Propagation of Action Potential An Action potential occurring in a local area of a membrane is to depolarize that area. Local current spreading from that area to an extent greater than necessary to cause neighboring voltage-gated sodium and potassium channels to open, resulting in the changes in the sodium and potassium conductance that then produce the action potential in these neighboring areas. This wave of depolarization occurs in a continuous fashion in un myelinated fibers. Propagation of Action Potential (Myelinated Axons & Non Myelinated Axons) In un myelinated Nerve: The action potential travels in a continuous manner along these axons. Because of a relatively uniform distribution of voltage sensitive Na+ and K+. In myelinated Nerve: The voltage -sensitive Na+ and K+ channels are not distributed uniformly. Na+ channels are clustered in high density in the axon membrane at the Node of Ranvier. K+ channels , on the other hand , tend to be localized in the “Internodal” area. Propagation of Action Potential Cont. Because the current flow through the insulating myelin is very slow and physiologically negligible, the action potential in myelinated axons jumps from one node to the next in a mode of conduction termed saltatory conduction. 15 16 Synapse A synapse is formed by junction between axonal terminal of one neuron( presynaptic neuron) and a second neuron ( post synaptic neuron). A Neuromuscular junction is the point of functional contact between axons and skeletal muscle. Types of Synapses Some synapses are located between an axon and a dendrite (axodendritic synapses, which tend to be excitatory), or a thorn, or mushroom-shaped dendritic spine which protrudes from the dendrite. This type is the most common representing 80-95% of all synapses. 2) Other synapses are located between an axon and a nerve cell body (axosomatic synapses, which tend to be inhibitory). 3) Other synapses are located between an axon terminal and another axon; these axoaxonic synapses modulate transmitter release by the postsynaptic axon. Synaptic transmission permits information from many presynaptic neurons to converge on a single postsynaptic neuron. Some large cell bodies receive several thousand synapses 1) Types of synapse based on nerve attachment Synaptic transmission Transmission of information or impulse (action potential) between neurons occurs at synapses. Communication between neurons usually occurs from the axon terminal of the transmitting neuron (presynaptic side) to the receptive region of the receiving neuron (postsynaptic side). This specialized intraneuronal Complex is a synapse, or synaptic junction. Types of synaptic transmission: A) Electrical transmission: Electrical synapse allow passage of electric current from one neuron to the other directly. This type of transmission is rare in humans. And is common in invertebrates. Transmission at electrical synapse does not involve neurotransmitter. Electrical transmission flows bidirectionally. B) Chemical transmission: Gap junction act as conductive pathway occurs by release of chemical substance (called neurotransmitter) from the presynaptic neuron to act on receptor on the membrane of the post synaptic neuron. Almost all synapses in human nervous system are of this type: chemical synapse. Chemical transmission is unidirectionally. Area of concentration of common neurotransmitter 24 Components of Synapse: 1) Presynaptic neuron 2)Synaptic cleft 3)Post synaptic membrane( post synaptic neuron) Steps of synaptic transmission Presynaptic terminal: Axons end in presynaptic terminals, or finger-like projections that are the transmitting elements of the neuron. Neurons transmit information about their activity via the release of chemicals called neurotransmitters from presynaptic terminals in to the synaptic cleft. The synaptic cleft is the space between two neurons, serve as the site for intraneuronal communication. The neurotransmitter diffuse from one side of the cleft to the other side and the neurotransmitter bind to receptors on the post synaptic neuron , gland , muscle. Steps of synaptic transmission When a nerve impulse arrives at the synapse, chemicals called neurotransmitters are released into the synaptic cleft. Neurotransmitter release is triggered by the electrotonic invasion of the action potential into the terminal. The influx of Ca2+ ions through voltage-gated channels that trigger the binding of synaptic vesicles at presynaptic active zones, Subsequent release of neurotransmitter by exocytosis(Active transport ) into the synaptic cleft. Each synaptic vesicle contains amount of neurotransmitter, and the number of released is directly correlated to the amount of Ca2+ entering the terminal. Neurotransmitters in the narrow synaptic cleft has conformational changes in agent-specific postsynaptic receptors, leading to an opening or closing of ion channels. Transmembrane changes mediated by inotropic receptors that quickly depolarize Pathophysiology of diseases affecting neurotransmission and action potential propagation Relatively common acquired hereditary disorders affect electrochemical transmission at the neuromuscular junction by either: 1)Reducing the presynaptic release of acetylcholine or 2)The postsynaptic action of acetylcholine.  There are a number of neurologic disorders, such as myasthenia gravis, Lambert-Eaton syndrome, or botulism, that represent a failure of neurotransmitter action at the presynaptic membrane, synapse, or at the receptors on the postsynaptic membrane. Myasthenia gravis Acquired autoimmune disorders affect transmission at the neuromuscular junction. Myasthenia gravis is an autoimmune disease affecting nicotinic acetylcholine receptors, Sign and symptoms: skeletal muscle weakness and fatigability in orbital, oropharyngeal, and limb musculature. Muscle weakness and fatigability is generally variable in severity and progressive through active hours of the day.  N.B: Nerve fiber are intact, and acetylcholine release at nerve terminal is normal. Antibodies attack the acetylcholine receptor in the postjunctional folds, leading to a progressive decreased muscle action potentials with repetitive stimulation. Structural changes of the postjunctional folds and diminished localization of the receptor at the crest of the folds also occur. How to overcome?????????? Increasing the efficacy of the action of acetylcholine in the neuromuscular cleft with acetylcholinesterase inhibitors decreases the severity of the symptoms. Lambert-Eaton syndrome Is a rare presynaptic disorder affecting neuromuscular transmission. Muscle weakness and fatigability is predominantly in proximal limb and trunk musculature as seen in Lambert-Eaton myasthenic syndrome owing to diminished presynaptic release of acetylcholine from the nerve terminals. Muscle excitability remains normal. 34 Demyelinated Disorders Guillain-Barré syndrome Physiologic level of lesion Demyelinating diseases affect PNS Schwann cells or CNS oligodendroglia. Guillain-Barré syndrome is acquired, acute onset inflammatory peripheral demyelinating neuropathy with axonal sparing. Multiple focal areas of demyelination of spinal roots and proximal nerve fibers result in very slow nerve conduction velocities reduced compound action potential amplitude in electrophysiologic recordings from affected nerves. Symptoms Symmetric and temporally progressive weakness in movements, first in the legs and then in the arms, gives the impression of an ascending paralysis. Difficulties in walking and rising from a chair are common complaints. Paralysis of respiratory muscles results in a high risk of respiratory failure. After treatment, functional recovery is possible by axonal remyelination. 37 38 39 40 41 42 43 44 Remyelination 46