1-Cytoskeletal components of the neurons and their functions during axonregeneration. Neurons contain a cytoskeleton consisting of neurofibrils, which determine theshape of the soma and the various processes extending from it, and which transportsubstances throught the neuron Microtubules and microtubule associated proteins (MAP) 25-28nm are narrow longitudinal tubes present in all neuronal processes. The tubesmantain shape, and also transport molecules such as neuro-transmitters from the soma to the axon terminals (anterograd transport), or from the terminals to the soma (retrograde transport). There are at least two types of axonal transport: (a) rapid, 400nm (b) slow, at less than 1 mm dayMicrofilaments 5-7 nm present in high concentrations as a meshwork beneath the membrane of the axon. Actin is a important protein in axon development , and causes the movement of the growth cone. Are a proliferation of globulin actin (G-actin) in the axolemma of the synapse, depolarisation of the microfilaments is a prerequesite for releasing of the trasmitters from the synapse vesicles. Neurofilamets 10nm Are the most abundant of the fibrillar elements in the neuron, and form the bones of the cytoskeleton they are largely spaced, having tide arms that keep them appart and provide neuronal stability seem to be invoolved in the transport mechanisms 3 different types of neurons: 1. unipolar 2. bipolar – concentrated mainly in periphery 3. multi-polar – formed by alfa and beta tubules according to size: 1. Type I Golgi (large+long axons) 2. Type II Golgi (small+short axons)
2-Types of axoplasmatic transports according direction and speed, theirfunctions in the intact neuron and during axon regeneration.Axonal Transport: Various secretory products produced in the cell body are carried to the axonterminals by special transport mechanism as in the same manner various constituents are carriedfrom the axon terminals to the cell body.Three main types of axonal transport are:⇒ fast anterograde transport⇒ slow anterograde transport⇒ fast retrograde transport.Fast anterograde transport is involved in the transport of materials that have afunctional role at the nerve terminals (e.g., precursors of peptide neurotransmitters,enzymes needed for the synthesis of small molecule neurotransmitters, andglycoproteins needed for reconstitution of the plasma membrane) are trasported fromthe cell body to the terminals. Polypeptides much larger than final peptideneurotransmitters (pre-propeptides) and enzymes needed for the synthesis of smallmolecule neurotransmitters are synthesized in the rough endoplasmic reticulum. Thevesicles formed in the Golgi apparatus for the axon terminals then become attached tothe microtubules and are transported by fast axonal transport (at a rate of 400 mm/d)into the nerve terminal. The rapid axonal transport depends on the microtubules. The microtubuleprovides a stationary track and a microtubule-associated ATPase (kinesin) forms across-bridge between the organelle to be moved and the microtubule. On one end,kinesin contains two globular heads that bind to the microtubule, and on the other end, ithas a fan-shaped tail that binds to the surface of an organelle. The organelle then movesby sliding of the kinesin molecule along the microtubuleSlow anterograde transport involves movement of neurofilaments and microtubulessynthesized in the cell body to the terminals at a rate of 5 mm/d. Soluble proteinstransported by this mechanism include actin, tubulin (which polymerizes to formmicrotubules), proteins that make up neurofilaments, myosin, and a calcium-bindingprotein (calmodulin).Fast retrograde transport is slower than the fast anterograde transport (about 200 mm/d). Rapid retrograde transport carries materials from the nerve terminals to the cellbody; the transported materials travel along microtubules. An example of transport by this mechanism is nerve growth factor (NGF), apeptide synthesized by a target cell and transported into certain neurons in order tostimulate their growth. Materials lying outside the axon terminals are taken up byendocytosis and transported to the cell body. Fast retrograde axonal transport is alsoinvolved in some pathological conditions. For example, the herpes simplex, polio, andrabies viruses and tetanus toxin are taken up by the axon terminals in peripheral nervesand carried to their cell bodies in the central nervous system (CNS) by rapid retrogradetransport.
3-Types of the neuronal synapses, their classification according morphology and neurotransmitters. Synapses needed for communication e.g.interneuronal synapses or intermuscular Direct synapses in neuromuscular junction Indirect synapses in autonomic postganglionic synapse Synapses may be either: 1. interneuronal connections 2. connections between the neuron and effector Interneuronal connectionsaccording to position of connections: - axodendritic and axo somatic synapses - axo-axonal and dendro – dendritic synapsesaccording to effect on postsynaptic element -excitatory synapses -inhibitory synapsesaccording to transmission of the excitation - eletric synapses: - reduced extracellular space - transport of info by ionic flow -continuity of cytoplasm -chemical synapses: -presynaptic termination - postsynaptic element - active zone - synaptic cleft – no continuity between pre and post- synapses -increased extracellular space
- transport of info by neurotransmitters4-Glial cell types and their participation in the ontogenetic development of theCNSThe supporting cells located in the CNS are called neuroglia or simply glial cells. Theyare nonexcitable and more numerous (5 to 10 times) than neurons. Neuroglia have beenclassified into the following groups: astrocytes, oligodendrocytes, microglia, andependymal cells. ⇒ Astrocytes Among the glial cells, astrocytes are the largest and have a stellate (star-shaped)appearance because their processes extend in all directions. Their nuclei are ovoid andcentrally located. The astrocytes provide support for the neurons, a barrier against thespread of transmitters from synapses, and insulation to prevent electrical activity of oneneuron from affecting the activity of a neighboring neuron. They are further subdivided into the following subgroups:a) Protoplasmic Astrocytes: These cells are present in the gray matter in closeassociation with neurons. Because of their close association with the neurons, they areconsidered satellite cells and serve as metabolic intermediaries for neurons. They giveout thicker and shorter processes, which branch profusely. Several of their processesterminate in expansions called end-feet. Abutting of processes of protoplasmicastrocytes on the capillaries as perivascular end-feet is one of the anatomical features ofthe blood-brain barrierb) Fibrous AstrocytesThese glial cells are found primarily in the white matter between nerve fibers. Severalthin, long, and smooth processes arise from the cell body; these processes show littlebranching. Fibrous astrocytes function to repair damaged tissue, and this process mayresult in scar formation.c) MĂĽller CellsThese modified astrocytes are present in the retina.
⇒ Oligodendrocytes These cells are smaller than astrocytes and have fewer and shorter branches.Their cytoplasm contains the usual organelles (e.g., ribosomes, mitochondria, andmicrotubules), but they do not contain neurofilaments. In the white matter,oligodendrocytes are located in rows along myelinated fibers and are known asinterfascicular oligodendrocytes. These oligodendrocytes are involved in themyelination process. The oligodendrocytes present in the gray matter are calledperineural oligodendrocytes. ⇒ Microglia These are the smallest of the glial cells. They usually have a few short branchingprocesses with thorn-like endings. These processes arising from the cell body give offnumerous spine-like projections. They are scattered throughout the nervous system.When the CNS is injured, the microglia become enlarged, mobile, and phagocytic. ⇒ Ependymal Cells Ependymal cells consist of three types of cells:a) Ependymocytes are cuboidal or columnar cells that form a single layer of lining inthe brain ventricles and the central canal of the spinal cord. They possess microvilli andcilia. The presence of microvilli indicates that these cells may have some absorptivefunction. The movement of their cilia facilitates the flow of the cerebrospinal fluid.b) Tanycytes are specialized ependymal cells that are found in the floor of the thirdventricle, and their processes extend into the brain tissue where they are juxtaposed toblood vessels and neurons. Tanycytes have been implicated in the transport of hormonesfrom the CSF to capillaries of portal system and from hypothalamic neurons to the CSF.
c) Choroidal epithelial cells are modified ependymal cells. They are present in thechoroid plexus and are involved in the production and secretion of CSF. They have tightjunctions that prevent the CSF from spreading to the adjacent tissues ⇒ PNS In the peripheral nervous system (PNS), Schwann cells provide myelin sheaths around axons. The myelin sheaths are interrupted along the length of the axons at regular intervals at the nodes of Ranvier. Thus, the nodes of Ranvier are + uninsulated and have a lower resistance. These nodes of Ranvier are rich in Na channels, and the action potential becomes regenerated at these regions. Therefore, the action potential traveling along the length of the axon jumps from one node of Ranvier to another. This type of propagation enables the action potential to conduct rapidly and is known as saltatory conduction. During the myelination, the axon comes in contact with the Schwann cell, which then rotates around the axon in clockwise or counterclockwise fashion. As the Schwann cell wraps around the axon, the cytoplasm becomes progressively reduced, and the inner layers of the plasma membrane come in contact and fuse together. ⇒ CNS Within the brain and the spinal cord, oligodendrocytes form the myelin sheathsaround axons of neurons. Several glial processes arise from one oligodendrocyte andwrap around a portion of the axon. The intervals between adjacent oligodendrocytes aredevoid of myelin sheaths and are called the nodes of Ranvier. Unlike in peripheralaxons, the process of an oligodendrocyte does not rotate spirally on the axon. Instead, itmay wrap around the length of the axon. The cytoplasm is reduced progressively, andthe sheath consists of concentric layers of plasma membrane. Unlike in peripheralnerves, one oligodendrocyte forms myelin sheaths around numerous (as many as 60)axons of diverse origins.
5-Glial cell types and their involvement in the ontogenetic development of the PNS. Glial cells of PNS originate from neural crest cells (plate) Schwmann cells produce myelin sheaths around myelinated axons of PNS neurons. Glial cells provide support as well as protection for neurons Most glial derived from ectodermal tissue (particularly neural tube and crest) The exception is microglia- derive from mesoderm . sattelite cells surrond neuronal cell bodies in PNS Schwmann cells of PNS promote regeneration of peripheral neurons A myelinated nerve fiber is one that is surronded by a myelin sheath. In the CNS thesupporting cell is called oligodendrocytes, in the PNS is called Schmann cell. The development of the myelin sheath provides an indication of the constructionof its lamellae. The body of Schmann cell forms a rolled up sheet of paper in which theaxon become embebedded. The structure develops, its margins become approximatedand eventually meet together, which results in duplication of the cell membrane – themesaxon (pair of parallel plasma membranes of a Schwann cell, marking the point ofedge-to-edge contact by the Schwann cell encircling the axon). This becomes spirallybound around the axon, probably big movement of the Scwmann cell around theenclosed axon. The beginning of the duplication lies on the inner side of the myelinsheath (inner mesaxon) and its end on the outer side (outer mesaxon). Another type ofsupporting cell are the satellite cells. Both Schwmann cellas and satellite cells developfrom neural crest cells. Myelinating Schwann cells begin to form the myelin sheath in mammals duringfetal development and work by spiraling around the axon, sometimes with as many as100 revolutions. A well-developed Schwann cell is shaped like a rolled-up sheet ofpaper, with layers of myelin in between each coil. The inner layers of the wrapping,which are predominantly membrane material, form the myelin sheath while theoutermost layer of nucleated cytoplasm forms the neurolemma. Only a small volume ofresidual cytoplasm communicates the inner from the outer layers. This is seenhistologically as the Schmidt-Lantermann Incisure. Since each Schwann cell can cover
about a millimeter (0.04 inches) along the axon, hundreds and often thousands areneeded to completely cover an axon, which can sometimes span the length of a body.6-Describe Wallerian degeneration and different reactions of the glial cells inCNS and PNS following injury. ⇒ Neuronal Injury/ Injury of the Neuronal Cell Body The neuronal cell body may be damaged by disease, ischemia (lack of bloodsupply), or trauma. In the CNS (the brain and spinal cord), the debris produced by neuronal damageis phagocytosed by microglia. The adjacent fibrous astrocytes proliferate, and theneurons are replaced by scar tissue. In the PNS, macrophages are responsible for the removal of the debris producedby neuronal damage, and the scar tissue is produced by the proliferation of thefibroblasts. Necrotic cell death is caused by acute traumatic injury that involves rapid lysisof cell membranes. Necrotic cell death is different from apoptosis. Apoptosis is definedas a genetically determined process of cell death and is characterized by shrinkage ofthe cell, cellular fragmentation, and condensation of the chromatin. During the processof formation of tissues from undifferentiated germinal cells in the embryo(histogenesis), more neurons (about 2 times more) are formed than the neurons presentin the mature brain. The excess number of neurons is destroyed during the developmentby apoptosis. The mechanism of apoptosis involves activation of a latent biochemicalpathway that is present in neurons and other cells of the body. The cellular debris afterneuronal cell death is removed by phagocytosis, which involves transport of solidmaterial into the cells (e.g., microglia) that remove the debris by indentation of the cellmembrane of the phagocyte and formation of a vesicle. Pinocytosis is similar tophagocytosis, except that liquid material is removed. Exocytosis involves fusion of avesicle inside the nerve terminal (e.g., a vesicle containing a neurotransmitter) with theplasma membrane and transportation of the contents of the vesicle outside the nerveterminal.
⇒ Axonal Damage/ Wallerian Degeneration This type of degeneration refers to the changes that occur distally to the site ofdamage on an axon. Because protein synthesis occurs primarily in the neuronal cellbody, the segment distal to the damaged site on the axon is affected profoundly.Initially, the axon swells up and becomes irregular. Later, the axon and the terminal arebroken down into fragments that are phagocytosed by adjacent macrophages andSchwann cells. Myelin is converted into fine drops of lipid material in the Schwanncells and is extruded from these cells; it is removed by macrophages in the PNS andmicroglial cells and invading macrophages in the CNS. Alterations may also be presentin the proximal segment of the axon up to the first node of Ranvier. ⇒ Chromatolysis Sectioning of an axon may produce changes in the cell body, and if the injury isclose to the cell body, the neuron may degenerate. The cell body swells up due to edemaand becomes round in appearance, and the Nissl substance gets distributed throughoutthe cytoplasm. The nucleus moves from its central position to the periphery due toedema. The degenerative changes start within hours and are complete within a relativelyshort time (about a week). ⇒ Anterograde Transneuronal Degeneration This type of degeneration occurs in the CNS when damage to a neuron results inthe degeneration of another postsynaptic neuron closely associated with the samefunction. For example, damage to an optic nerve results in the degeneration of thelateral geniculate neurons receiving inputs from this nerve. ⇒ Retrograde Transneuronal Degeneration This type of degeneration occurs in neurons sending inputs to an injured neuron.In this situation, terminals of the neuron synapsing with a chromatolytic neuronwithdraw and are replaced by processes of glial cells. The neuron, from which theinputs to the chromatolytic neuron arise, eventually degenerates.
⇒ Recovery of Neuronal Injury (Regeneration) If the damage to the neurons is not severe and they survive the injury,regeneration is possible, but complete recovery may take as long as 3 to 6 months.Within about 3 weeks, the swelling of the cell subsides, the nucleus occupies a centralposition in the cell body again, and the Nissl bodies are normally distinguished. Theseevents indicate that protein synthesis has been restored in the neuronal cell body. Insevere damage, although sprouting occurs in axons in the CNS, this process ceaseswithin a short time (about 2 weeks). In this situation, normal functions of the neurons inthe CNS are not restored. However, in peripheral nerves, an axon can regeneratesatisfactorily if the endoneurial sheaths are intact. In this situation, the regeneratingaxons reach the correct destination, and the chances of recovery of function arereasonable. The growth rate of an axon has been estimated to be 2 to 4 mm per day.
7-Describe developmental zones of the neural tube during histogenesis of the CNS, describecell populations originating from the neural crest. The nervous system develops from ectoderm, the surface layer of embryonictissue. By the third to fourth week of embryonic development, the notochord, ofmesodermal origin, induces the development of the neural plate. By the third to fourthweek of embryonic development, there is a high rate of cell proliferation. As such, theanterior part of the notochord (of mesodermal origin) begins to thicken, and thus, theneural plate is formed by the third week of fetal life. The neural plate continues tothicken over the following week and expands laterally. As it expands, the faster growinglateral edges of the plate accumulate in a dorsal position as neural folds. As this plategrows and widens, it forms a shallow groove along its longitudinal axis known as theneural groove. The posterior end of the neural plate, which is narrower than the anteriorend, will ultimately become the spinal cord, whereas the broader, anterior end willbecome the brain. As this plate grows and widens, the neural groove becomes deeper. Inthe process of its forming and deepening, some of the cells located in the lateral marginof the neural groove separate and migrate to a dorsal position to become the neuralcrest. As the embryo grows, the neural folds fuse along the midline, thus forming aneural tube. The neural tube consists of three layers: 1. an inner layer called the ventricular layer, which is in contact with the cavity of the neural tube; 2. an intermediate layer called the mantle layer; and 3. an outer layer called the marginal layer. The ventricular zone is the major proliferative layer and also the first layer of theforming neural tube to appear. The second layer to form is the marginal layer, followedby the mantle layer. Early in development, the wall of the neural canal becomesthickened, in part, by the formation of young or immature neurons that have yet tocompletely differentiate (sometimes called neurocytes) in the mantle layer. Because this
layer contains the primary cell bodies of neurons, it will ultimately become the graymatter of the spinal cord. Axons associated with cells in the mantle layer will grow intothe marginal layer. Histogenesis of CNS: 1. Ventricular zone -separates precursors for neurons and glial cells− -migration of nuclei to base of ventricular cells 2. Marginal zone− -no cell bodies - axons of neurons from intermediate zone invade this zone− 3. Intermediate zone− - forms a interface of ventricular and intermediate zones - no migration of nuclei Cell populations originating from neural crest: During folding of neural crest, groups of cells appear along neural groove, neural crest cells Some of these cells give rise sensory ganglia (dorsal root ganglia) cells of neural crest differentiate into Schwmann cells , pigment cells, meninges and odontoblasts.
8-Describe trophic interactions among the neurons and their target tissue, describegeneral features of neurotrophic factors. Trophism refers to the ability of certain molecules called trophic (nutritional)factors, to promote cell survival. Neurotrophic factors are polypeptides that supportsurvival, growth, regeneration, and plasticity of neurons. Most types of neuron aregenerated in excessive numbers, followed later by the death of “surplus” cells soon afteraxons reach the vicinity of their target. This type of neuronal cell death is regarded to bea consequence of the competition for the limited amount of neurotrophic factorsreleased by target cells (e, g., embryonic muscle cells). This is an adaptive means ofadjusting the number of neurons of each type to the number of target cells to beinnervated. The “trophic effect” exerted on neurons is illustrated by the trophicinfluences of “taste nerve fibers” upon the taste buds. Not only do the gustatorynerve fibers convey taste information, but they also have critical roles in both themaintenance and regeneration of taste buds. Following transection of the gustatorynerve fibers, the taste buds degenerate. In time, if and when the transected fibersregenerate into the oral epithelium, new functional taste buds will differentiate fromepithelial cells, Presumably, only taste fibers elaborate the essential trophic factors toinduce the formation of new taste buds from the oral epithelium. Trophic activity couldoccur at any time from embryonic life through adulthood. Although a progressivereduction in activity occurs with age, it is never completely lost. In addition to trophiceffects, there are tropic effects. Tropism refers to the ability of certain molecules topromote or to guide the outgrowth and directional growth or extension of neuronalprocesses (axons and dendrites). Neurotrophins are a class among many neurotrophicfactors that have important roles in the survival of neurons and have widespread effectsthroughout the CNS and peripheral nervous system (PNS). Neurotrophins include nervegrowth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3),and neurotrophin 4/5 (NT 4/5). Examples of related trophic factors include fibroblastgrowth factor (FGF), the epidermal growth factor family (EGF) and cytokines. Thecytokines (e.g., interleukin, a leukemia-inhibitory factor) are extracellular or membrane-anchored polypeptides that mediate communication between cells via cell surface
receptors. Trophic factors, as indicated, have roles in promoting the successive stages inthe cycle of neuronal differentiation, growth, survival, and programmed cell death 9-Selective neuronal death during ontogenic development of the nervoussystem; describe a mechanism and its significance. Programme cell death is an integral part of animal tissue development.Development of an organ or tissue is often preceded by the extensive division anddifferentiation of particular cell, with the resultant mass is then arranged in the correctform with help of apoptosis. Unlike cellular death (caused by hypoxia or other various injury), apoptosisresults in cell shrinkage and fragmentation. This allows the cells to be efficientlyphagocytosed and ther components removed without releasing of potentially harmfulintracellular substances into the surrounding tissue. If a neuron (and especially its DNA) gets damaged by a virus or a toxin,apoptosis destroys and silently removes these sick genes, which may serve to protectsurrounding healthy neurons. More importantly, apoptosis is a natural part ofdevelopment of the immature central nervous system. One of the many wonders of thebrain is the built-in redundancy of neurons early in development. These neuronscompete vigorously to migrate, innervate target neurons, and drink trophic factorsnecessary to fuel this process. Apparently, there is survival of the fittest, because up to50% of many types of neurons normally die in this time of brain maturation. Apoptosisis a natural mechanism to eliminate the unwanted neurons without making as big amolecular mess as doing it via necrosis. Cell death via apoptosis is a prominent feature in mammalian neuraldevelopment. Recent studies into the basic mechanism of apoptosis have revealedbiochemical pathways that control and execute apoptosis in mammalian cells. Proteinfactors in these pathways play important roles during development in regulating thebalance between neuronal life and death. Additionally, mounting evidence indicatessuch pathways may also be activated during several neurodegenerative diseases,resulting in improper loss of neurons.
10-Describe molecular mechanisms for axon navigation to the target tissue duringdevelopment and regeneration of the nervous system. Molecular mechanisms of axon guidance: 1. Contact inhibition – adhesion (permissive and non-permissive substrates) 2. Fasciculation (small, involuntary muscle contractions due to spontaneous discharges) 3. Chemotropism (movement caused by chemical stimulus) Cellular and molecular mechanisms for regeneration of nervous system:Different reaction of the CNS and PNS neurons to injury of neural processes.PNS neurons: anabolic processes due to increased synthesis of cytoskeleton andmembrane proteins and increased synthesis of RNA.CNS neurons: reaction with distinct regressive mechanisms(atrophy) and destructionof neurons. Decreased synthesis if the RNA
11-Describe structural components of the hematoencephalic barrier, functionalsignificance of HEB. Meningeal barriers is formed by arachnoid placed between intradural blood vessels and CSF in the subarachnoid space. Blood-brain barrier, which is located at the interface between the capillary wall and brain tissue. The blood-brain barrier consists of: (1) endothelial cells lining the capillary wall with tight junctions between them, (2) processes of astrocytes abutting on the capillaries as perivascular end-feet, (3) a capillary basement membrane. This arrangement of different cells or their processes prevents the passage of large molecules from the blood into the extracellular space between the neurons and neuroglia and forms the anatomical basis of the blood-brain barrier. One of the beneficial functions of the blood-brain barrier is to prevent entry of blood-borne foreign substances into the brain tissue. However, the existence of this blood-brain barrier also presents a problem when the goal is to deliver drugs into the CNS. In other organs, tight junctions do not exist between the neighboring endothelial cells lining the capillaries. The capillaries and the ependymal epithelial cells of the choroid plexus form the blood-CSF barrier between the blood and CSF. The presence of this barrier results in distinct differences of concentration of some molecules in the blood and CSF
12-Describe the CNS liquid compartments and their barriers. Fluid (liquid) compartments: Interstitial fluid: bathing neurons and glial cells within CNS CSF: in subarachnoid space and ventricular system. Blood: in the meningeal vessels Intracellular fluid: in neurons and glial cells CSF: There are four main functions of the CSF. (1) The brain and spinal cordfloat in the CSF because the specific gravities of these central nervous system (CNS)structures are approximately the same. This buoyant effect of the CSF results inreduction of traction exerted upon the nerves and blood vessels connected with theCNS. (2) The CSF provides a cushioning effect on the CNS and dampens the effects oftrauma. (3) The CSF also serves as a vehicle for removal of metabolites from the CNS.(4) Under normal conditions, the CSF provides a stable ionic environment for the CNS.However, the chemical composition of the CSF may change in certain situations such asadministration of drugs that cross the blood-brain barrier. The cerebral barriers: Meningeal barriers: is formed by arachnoid placed between intradural blood vessels and CSF in the subarachnoid space
13- Describe individual mechanisms of transportation throught thehematoencephalic barrier.Transport mechanisms of blood brain barrier (BBB)⇒ Passive diffusion: lipid soluble substances pass throught the barrier, such as O2, Co2, barbiturates, alcohol⇒ Facilitated diffusion: substances that penetrate membranes by carrier or mediated mechanisms. This category of transport carries more molecules and rapidly and without consumption of enegy.⇒ Active transport: consumption of energy, and uses carrier molecules. It proceeds against a concentration gradient. E.g amino acids or extracellular potassium. Moves molecules from the brain and CSF into blood plasma against a concentration gradient.⇒ Transcytosis: is selective transport by means of the coated vesicles that fuse to form trasnsendothelial canal, e.g. Fe bind transferin ehich has Fe receptors The combination of the specialized cell membrane of the endothelial cells linkedby intercellular tight junctions is the hallmark of the BBB. This duo effectively excludesby blocking the passage of many substances across the capillary wall. The permeabilityproperty can be enhanced by the state of phosphorylation of the proteins of the cell–celladherens junctions. The cadherin proteins of the adherens junctions also act as a sig-nalling component between endothelial cells through linkages with the cytoskeletal pro-tein filaments of the endothelial cells. The presence of so few pinocytotic vesicles with-in the endothelial cells is indicative that the transcellular movement by vesicles acrossthe BBB (transendocytosis) is both relatively deficient and slow. However, the selectivepassage of substances is related to the presence of high concentrations of carriermedi-ated transport systems that act as transporters for glucose, essential amino acids, otherrequired nutrients, and macromolecules. These ensure the passage of essential sub-stances from the blood to the CNSThe combination of the specialized cell membrane ofthe endothelial cells linked by intercellular tight junctions is the hallmark of the BBB.This duo effectively excludes by blocking the passage of many substances across the ca-pillary wall. The permeability property can be enhanced by the state of phosphorylationof the proteins of the cell–cell adherens junctions. The cadherin proteins of the adherensjunctions also act as a signalling component between endothelial cells through linkageswith the cytoskeletal protein filaments of the endothelial cells. The presence of so fewpinocytotic vesicles within the endothelial cells is indicative that the transcellular move-ment by vesicles across the BBB
14- Describe the CNS structures without total hematoencephalic barrier and theirfunction. There are seven structures in the CNS that lack a blood-brain barrier. Calledcircumventricular organs, they are the area postrema, pineal body, subcommissuralorgan, subfornical organ, organum vasculosum of lamina terminalis (OVLT),neurohypophysis (the posterior pituitary gland), and the median eminence. They lack tight junctions in their capillaries. Instead, they have fenestratedcapillaries, capillary loops, and large perivascular spaces that permit the passage oflarger circulating molecules into the adjacent brain tissue. It is believed that somecirculating hormones consisting of large molecules reach their target areas in the brainvia the circumventricular organs. For example, the subfornical organ lies in the roof ofthe third ventricle. Blood-borne angiotensin II reaches the subfornical organ readilybecause of the lack of the blood-brain barrier in this organ and induces thirst for overallregulation of fluid balance and cardiovascular homeostasis. Functional effects⇒ Acts as homeostatic organs: e.g neurohypophyses releases oxitocin and vasopressin (ADH)⇒ Acts as as chemoreceptors e.g. Angiotensin II may act to increase blood pressure⇒ Acts as osmoreceptors⇒ The area postrema is the vomiting centre of the brain, detect noxious substances in the blood and stimulate vomiting in order to rid that substances from the body
15- Measuring of the cerebral blood flow The metabolic demands of the brain must be met with the blood supply to thisorgan. Normal cerebral blood flow is about 50 mL/100 g of brain tissue/min. Thus, abrain of average weight (1500 g) has a normal blood flow of 750 mL/min. Even a briefinterruption of the blood supply to the CNS may result in serious neurologicaldisturbances. A blood flow of 25 mL/100 g of brain tissue/min constitutes ischemicpenumbra (a dangerously deficient blood supply leading to loss of brain cells). A bloodflow of 8 mL/100 g of brain tissue/min leads to an almost complete loss of functionalneurons. Consciousness is lost within 10 seconds of the cessation of blood supply to thebrain. Freks principle: Cerebral blood flow can be measured by determining the amount of nitrousoxide removed from the blood stream (Qx) per unit of time and dividing that value bythe difference between the concentration in the atrial blood (Ax) and the in the venousblood (Vx): Qx CBF= --------------- [Ax] - [Vx]Qx= amount of nitrous oxide removed from the bloodAx= concentration in atrial bloodVx= concentration in the venous bloodAverage blood flow in young adults is 54ml/100g/minAverage brain weight 1400g hence we have a blood flow to brain corresponding to756ml/minFactors that affect cerebral blood flow : 1) Intracranial pressure 2) Blood viscosity 3) Mean venous pressure 4) Mean atrial pressure 5) Constriction and dilation of cerebral arterioles
16 – Blood flow in various parts of the brain Arterial supply of the brain: Blood supply to the brain is derived from two arteries: (1) the internal carotidartery and (2) the vertebral artery. These arteries and their branches arise in pairs thatsupply blood to both sides of the brain. The basilar artery is a single artery located in themidline on the ventral side of the brain. The branches of the basilar artery also arise inpairs. Internal Carotid Artery This artery arises from the common carotid artery on each side at the level of thethyroid cartilage and enters the cranial cavity through the carotid canal. Branches:⇒ The Ophthalmic Artery: enters the orbit through the optic foramen and gives rise to the central artery of the retina, which supplies the retina and cranial dura. Interruption of blood flow in the ophthalmic artery causes loss of vision in the ipsilateral eye.⇒ The Posterior Communicating Artery: arises at the level of the optic chiasm and travels posteriorly to join the posterior cerebral arteries. Small branches arising from this artery supply blood to the hypophysis, infundibulum, parts of the hypothalamus, thalamus, and hippocampus.⇒ The Anterior Choroidal Artery: arises near the optic chiasm and supplies the choroid plexus located in the inferior horn of the lateral ventricle, the optic tract, parts of the internal capsule, hippocampal formation, globus pallidus, and lateral portions of the thalamus.⇒ The Anterior Cerebral Artery: The anterior cerebral artery travels rostrally through the interhemispheric fissure. It supplies blood to the medial aspect of the cerebral hemisphere, including parts of the frontal and parietal lobes. This artery also supplies blood to the postcentral gyrus and precentral gyrus. Occlusion of one of the anterior cerebral arteries results in loss of motor control (paralysis) and loss of sensation in the contralateral leg. Other structures supplied by the anterior cerebral artery include the olfactory bulb and tract, anterior hypothalamus, parts of caudate nucleus, internal capsule, putamen, and septal nuclei.⇒ The Anterior Communicating Artery: at the level of the optic chiasm, the anterior communicating artery connects the anterior cerebral arteries on the two sides. A group of small arteries arising from the anterior communicating and anterior cerebral arteries penetrates the brain tissue almost perpendicularly and supplies blood to the anterior hypothalamus, including preoptic and suprachiasmatic areas.⇒ The Medial Striate Artery (Recurrent Artery of Heubner): arises from the anterior cerebral artery at the level of the optic chiasm and supplies blood to the anteromedial part of the head of the caudate nucleus and parts of the internal capsule, putamen, and septal nuclei. The medial striate and the lenticulostriate arteries penetrate the perforated substance.⇒ The Middle Cerebral Artery: at the level just lateral to the optic chiasm. Branches of the middle cerebral artery supply blood to the lateral convexity of the cerebral hemisphere including parts of the temporal, frontal, parietal, and occipital lobes.
Vertebro-Basilar Circulation:This system includes the two vertebral arteries, the basilar artery (which is formed bythe union of the two vertebral arteries), and their branches. This arterial system suppliesthe medulla, pons, mesencephalon, and cerebellum. Braches:⇒ The vertebral artery: on each side is the first branch arising from the subclavian artery. It enters the transverse foramen of the sixth cervical vertebrae, ascends through these foramina in higher vertebra, and eventually enters the cranium through the foramen magnum. In the cranium, at the medullary level, each vertebral artery gives off the anterior spinal artery, the posterior inferior cerebellar artery, and the posterior spinal artery.⇒ The Anterior Spinal Artery: at the confluence of the two vertebral arteries, two small branches arise and join to form a single anterior spinal artery. This artery supplies the medial structures of the medulla, which include the pyramids, medial lemniscus, medial longitudinal fasciculus, hypoglossal nucleus, and the inferior olivary nucleus.⇒ The Posterior Inferior Cerebellar Artery (PICA): arises from the vertebral artery and supplies the regions of the lateral medulla that include the spinothalamic tract, dorsal and ventral spinocerebellar tracts, descending sympathetic tract, descending tract of cranial nerve V, and nucleus ambiguus.⇒ The Posterior Spinal Artery (PSA): It is the first branch of the vertebral artery in the cranium in about 25% of cases. However, in a majority of cases (75%), it arises from the posterior inferior cerebellar artery. In the caudal medulla, this artery supplies the fasciculus gracilis and cuneatus as well as the gracile and cuneate nuclei, spinal trigeminal nucleus, dorsal and caudal portions of the inferior cerebellar peduncle, and portions of the solitary tract and dorsal motor nucleus of the vagus nerve.⇒ The Basilar Artery: The two vertebral arteries join at the caudal border of the pons to form the single basilar artery.⇒ The Anterior Inferior Cerebellar Artery (AICA): is the most caudal branch arising from the basilar artery. The AICA supplies the ventral and inferior surface of the cerebellum and lateral parts of the pons.⇒ The labyrinthine (internal auditory) artery: is usually a branch of the AICA and supplies the cochlea and labyrinth.⇒ The Pontine Arteries: Several pairs of pontine arteries arise from the basilar artery. Some pontine arteries (the paramedian arteries) enter the pons immediately and supply the medial portion of the lower and upper pons. Some pontine arteries (the short circumferential arteries) travel a short distance around the pons and supply substantia nigra and lateral portions of the midbrain tegmentum.⇒ The superior cerebellar artery: arises just caudal to the bifurcation of the basilar artery and supplies the rostral level of the pons, caudal part of the midbrain, and superior surface of the cerebellum. ⇒ The posterior cerebral arteries arise at the terminal bifurcation of the basilar artery. Branches of the posterior cerebral arteries supply most of the midbrain, thalamus, and subthalamic nucleus. Cerebral Arterial Circle (Circle of Willis)
The cerebral arterial circle surrounds the optic chiasm and the infundibulum of thepituitary. It is formed by the anastomosis of the branches of the internal carotid arteryand the terminal branches of the basilar artery. The anterior communicating arteryconnects the two anterior cerebral arteries, thus forming a semicircle. The circle iscompleted as the posterior communicating arteries arising from the internal carotidarteries at the level of the optic chiasm travel posteriorly to join the posterior cerebralarteries that are formed by the bifurcation of the basilar artery. The circle of Willis ispatent in only 20% of individuals. When it is patent, this arterial system supplies thehypothalamus, hypophysis, infundibulum, thalamus, caudate nucleus, putamen, internalcapsule, globus pallidus, choroid plexus (lateral ventricles), and temporal lobe.
17- Regulation of cerebral circulation. Brain metabolism.Brain metabolism:3 metabolic factors have potent effect on control of cerebral blood flow (CBF) :⇒ Increase in [CO2] leads to increase of CBF. CO2 + H2O H2CO3 HCO3- + H+ AND the H+ causes the dilation of cerebral vessels⇒ Increase in H+ leads to increase in CBF⇒ Decrease in O2 leads increase CBF via vasodilationThe brain (2% of the total body weight) receives about 15% of the cardiac output andconsumes about 20% of the total O2 consumption.The brain is highly sensitive to disturbances of the blood supply. Ischaemia lastingseconds causes symptoms and lasting for few minutes causes irreversible damage.The caliber of the arterioles is regulated by:⇒ Local vasodilators; metabolites (e.g. CO2)~⇒ Vasoactive substances produced by the endothelium, circulating peptides such as angiotensin II⇒ Vasomotor nerves⇒ Autoregulation mechanisms (the systemic blood pressure increases, but the cerebral blood flow remains constant by: a) intraluminar pressure within the arterioles elicits direct myogenic responde b) hypocapnia causes arterial vasoconstrictionIntracranial pressure:⇒ cerebral vessels are compressed even if there is no increase in intracranial pressure⇒ any change in venous pressure causes a similar change in intracranial pressure. A rise in venous pressure decreases cerebral blood flow.⇒ Cerebreal circulation has strong sympathetic innervation extending from the superior cervical ganglion⇒ Brain extremely sensitive to hypoxia⇒ Ammonia very toxic to nerve cells and leaves the brain in the form of glutamine
18- Formation and absorption of cerebrospinal fluid. Function of cerebrospinalfluid. Formation of the Cerebrospinal fluid: About 70% of the CSF present in the brain and spinal cord is produced by thechoroid plexuses. The remaining 30% of CSF, which is secreted by the parenchyma ofthe brain, crosses the ependyma (a single layer of ciliated columnar epithelial cellslining the ventricular system) and enters the ventricles. The formation of CSF is anactive process involving the enzyme carbonic anhydrase and specific transportmechanisms. The formation of the CSF first involves filtration of the blood through thefenestrations of the endothelial cells that line the choroidal capillaries. However, themovement of peptides, proteins, and other larger molecules from this filtrate into theCSF is prevented by the tight junctions that exist in the neighboring epithelial cells thatform the outer layer of the choroid plexus. Energy-dependent active transportmechanisms are present in the choroidal epithelium for transporting Na+ and Mg2+ ionsinto the CSF and for removing K+ and Ca2+ ions from the CSF. Water flows across theepithelium for maintaining the osmotic balance. Normally, the rate of formation of CSFis about 500 mL/day and the total volume of CSF is 90 to 140 mL, of which about 23mL is in the ventricles, and the remaining is in the subarachnoid space. Circulation: The movement of CSF is pulsatile. It flows from the lateral ventricles into thethird ventricle through the foramina of Monro where it mixes with more CSF. Then, itflows through the cerebral aqueduct (aqueduct of Sylvius) into the fourth ventricle,where additional CSF is secreted. The fluid leaves the ventricular system via theforamina of Luschka and Magendie and enters the cerebellomedullary cistern (cisternamagna). The CSF then travels rostrally over the cerebral hemisphere where it enters thearachnoid villi. Absorption: is made throught the arachidonic vili. The CSF drains into duralvenous sinuses, there are valves here, so fluid flows only from vili to veins wherepressure difference is appropriate. Functions: There are four main functions of the CSF. (1) The brain and spinal cord float in the CSF because the specific gravities ofthese central nervous system (CNS) structures are approximately the same. Thisbuoyant effect of the CSF results in reduction of traction exerted upon the nerves andblood vessels connected with the CNS. (2) The CSF provides a cushioning effect on the CNS and dampens the effects oftrauma. (3) The CSF also serves as a vehicle for removal of metabolites from the CNS. (4) Under normal conditions, the CSF provides a stable ionic environment forthe CNS. Composition:Normally, very little protein is present in the CSF, and this is the primary differencebetween CSF and blood serum. The concentrations of glucose, as well as
19 – Resting potential of the neuron Resting membrane potential: When a neuron is not generating actionpotentials, it is at rest. When the neuron is at rest, its cytosol along the inner surface ofits membrane is negatively charged compared with the charge on the outside. Typically,the resting membrane potential (or resting potential) of a neuron is -65 millivolts (mV). The potential difference across the cell membrane during resting state is calledthe resting membrane potential. The lipid bilayer of the neuronal membrane maintainsthis separation of charges by acting as a barrier to the diffusion of ions across themembrane. The ion concentration gradients across the neuronal membrane areestablished by ion pumps that actively move ions into or out of neurons against theirconcentration gradients. The selective permeability of membranes is due to the presenceof ion channels that allow some ions to cross the membrane in the direction of theirconcentration gradients. The ion pumps and ion channels work against each other in thismanner. If the neuronal membrane is selectively permeable to only a K+ ion, this ionwill move out of the neuron down its concentration gradient. Therefore, more positivecharges accumulate outside the neuron. The fixed negative charges inside the neuronimpede the efflux of positively charged K+ ions, and excess positive charges outside theneuron tend to promote influx of the K+ ions into the neuron due to the electrostaticforces. The opposite charges attract, while similar charges repel each other. Thus, twoforces are acting on the flow of K+ ions out of the neuron; a higher concentration insidethe neuron (concentration gradient) tends to expel them out of the neuron, while theelectrostatic forces tend to prevent their flow out of the neuron. When the two opposing forces are equal, K+ concentrations inside and outsidethe neuron are in equilibrium. The value of the membrane potential at this time is calledthe K+ equilibrium potential. Thus, if the neuronal membrane contained only K+channels, the resting membrane potential would be determined by the K+ concentrationgradient and would be equal to the equilibrium potential for K+ ions (approximately -80mV). However, as stated earlier, the resting membrane potential of a neuron is usually-65 mV. This is because neurons at rest are permeable to the Na+ ion also. The Na+ ionstend to flow into the neuron due to two forces: (1) concentration gradient of Na+ ions(extracellular Na+ concentration is much higher than its intracellular concentration) and(2) electrostatic forces (there is an excess of positive charges outside and an excess ofnegative charges inside the neuron). Due to the influx of Na+ ions, the resting membranepotential deviates from that of the K+ equilibrium potential (i.e., it becomes -65 mVinstead of -80 mV). However, the membrane potential does not reach the equilibrium potential for +Na . The reason for the neurons inability to attain a resting membrane potential closerto the Na+ equilibrium potential is that the number of open nongated Na+ channels ismuch smaller than the number of open nongated K+ channels in the resting state of aneuron. The permeability of Na+ is small despite large electrostatic and concentrationgradient forces tending to drive it into the neuron. To maintain a steady restingmembrane potential, the separation of charges across the neuronal membrane must bemaintained at a constant. This is accomplished by the Na+-K+ pump described earlier. Goldman equation: since the neuronal membrane is permeable to more thanone ion, the goldman equation is used to calculate membrane potential. This equationtakes into account the contribution of the permeability of each ion and its extra- andintracellular concentration. Nerst equation: is used to calculate equilibrium potential of an ion that ispresent on both sides of the cell membrane.
20- Receptor, synaptic and action potential-descriptionReceptor potential: whatever the stimulus that excites the receptor, its immediateeffect is to arrange the membrane potential of the receptor. This change is calledreceptor potential.Different receptors can be excited, either: a) By mechanical deformation that stretches the receptor membrane and opens ion channels. b) By application of a chemical to the membrane c) By change of temperature d) By eletromagnetic radiationWhen the receptor potential rises above the threshold for eliciting an action potential,the the action potential begins to appear. The more the receptor potential rises above thethreshold level, the greater becomes the action potential frequencySynaptic potential: an interaction of a transmitter on postsynaptic neuron initiates asynaptic potential.Can be either: EPSP (excitatory postsynaptic potential) IPSP (inhibitory postsynaptic potential)Action potential: rapid change in the membrane potential. It begins with a suddenchange from the normal resting membrane potential to a positive membrane potential. When a neuron receives an excitatory input, the neuronal membrane isdepolarized, resulting in an opening of some voltage-gated Na+ channels and influx ofNa+ . The accumulation of positive charges due to influx of Na+ promotes depolarizationof the neuronal membrane. When the membrane potential reaches threshold potential,the chances of generating an action potential are about 50%. However, when themembrane is depolarized beyond the threshold potential, a sufficient number of voltage-gated Na+ channels open, relative permeability of Na+ ions is greater than that of K+ions, and action potentials are generated with certainty. During the rising phase of the action potential, there is a rapid depolarization ofthe membrane due to increased permeability of Na+. The depolarization continues sothat the membrane potential approaches the Na+ equilibrium potential. The part of theaction potential where the inside of the neuron is positive relative to the outside is calledthe overshoot. Towards the end of the rising phase of the action potential, voltage-gatedNa+ channels are inactivated, and the influx of Na+ through these channels is stopped.During the falling phase of the action potential, the neuron is repolarized by opening ofvoltage-gated K+ channels, which allows increased efflux of K+ from the neuron throughthese channels. The opening of voltage-gated K+ channels is also caused bydepolarization of the neuronal membrane. Because these voltage-gated K+ channelsopen with a delay (about 1 msec) after the membrane depolarization and their openingrectifies the membrane potential, they are called delayed rectifier K+ channels. At theend of the falling phase, the membrane potential is more negative than the restingpotential because of increased K+ permeability caused by the opening of the delayedrectifier K+ channels in addition to the already present resting K+ permeability throughnongated channels. The permeability is closer to the equilibrium potential of K+ becausethere is little Na+ permeability during this period. This portion of the action potential iscalled after-hyperpolarization or undershoot. Once after-hyperpolarization has occurred,the resting membrane potential is restored gradually as the voltage-gated K+ channelsclose again.
21 – Ionic basis of membrane potential changes The resting membrane potential of a neuron is usually -65 mV. At rest, Na+influx into the neuron through open nongated Na+ channels is balanced by the efflux ofK+ through open nongated K+ channels. Thus, the membrane potential remains constantcloser (but not equal) to the K+ equilibrium. When a neuron receives an excitatory input, the neuronal membrane isdepolarized, resulting in an opening of some voltage-gated Na+ channels and influx ofNa+. Na+ channels are normally closed. The accumulation of positive charges due toinflux of Na+ promotes depolarization of the neuronal membrane. When the membranepotential reaches threshold potential, the chances of generating an action potential areabout 50%. However, when the membrane is depolarized beyond the thresholdpotential, a sufficient number of voltage-gated Na+ channels open, relative permeabilityof Na+ ions is greater than that of K+ ions, and action potentials are generated withcertainty. Generation of an action potential is an all-or-nothing phenomenon. Becausethe concentration of Na+ channels is relatively high at the axon hillock, this is the site ofgeneration of action potentials in a neuron. During the rising phase of the action potential generation, there is a rapiddepolarization of the membrane due to increased permeability of Na+. Thedepolarization continues so that the membrane potential approaches the Na+ equilibriumpotential. The part of the action potential where the inside of the neuron is positiverelative to the outside is called the overshoot. Towards the end of the rising phase of theaction potential, voltage-gated Na+ channels are inactivated, and the influx of Na+through these channels is stopped.During the falling phase of the action potential, the neuron is repolarized by opening ofvoltage-gated K+ channels, which allows increased efflux of K+ from the neuron throughthese channels. The opening of voltage-gated K+ channels is also caused bydepolarization of the neuronal membrane. Because these voltage-gated K+ channelsopen with a delay (about 1 msec) after the membrane depolarization and their openingrectifies the membrane potential, they are called delayed rectifier K+ channels. At theend of the falling phase, the membrane potential is more negative than the restingpotential because of increased K+ permeability caused by the opening of the delayedrectifier K+ channels in addition to the already present resting K+ permeability throughnongated channels. The permeability is closer to the equilibrium potential of K+ becausethere is little Na+ permeability during this period. This portion of the action potential iscalled after-hyperpolarization or undershoot. Once after-hyperpolarization has occurred,the resting membrane potential is restored gradually as the voltage-gated K+ channelsclose again. The sodium channel exists in the following three states: resting, activated, orinactivated. • Resting state: During this state, the activation gate closes the channel pore while the inactivation gate is open. With the channel pore closed, Na+ cannot flow into the neuron. • Activated state: During the rising phase of action potential, both activation and inactivation gates are open, and Na+ ions flow into the neuron. • Inactivated state: During this state, the inactivation gate closes the channel pore while the activation gate is still open. Even though the activation gate is open, Na+ cannot flow into the neuron. The neuron cannot be activated until the
22- Ion channels in neurons – their distributionsIon Channels:. Ion channels are made up of proteins that are embedded in the lipid bilayer ofthe neuronal membrane across which they span. They are characterized by the followinggeneral properties. • The flow of ions through the channels does not require metabolic energy; the flow is passive. • The electrochemical driving force across the membrane, but not the channel itself, determines the direction and eventual equilibrium of this flow. • The ionic charge determines whether a channel allows an ion to flow through; some channels allow cations while others allow anions to flow through them. • Most cation-selective channels allow only one ion species (e.g., Na+ or K+ or Ca2+) to flow through them. However, some channels allow more than one ion species to flow through them. For example, when L-glutamate (an excitatory amino acid neurotransmitter) activates an N-methyl-D-aspartic acid (NMDA) receptor, both Na+ and Ca2+ ions flow through the NMDA receptor channel into the neuron. • Most anion-selective channels allow only Cl- to flow through them. • Some blockers can prevent the flow of ions through the ion channels. For example, phencyclidine (PCP, or Angel Dust) blocks the NMDA receptor channel. Classification of Ion Channels: Nongated Channels: Although nongated channels are capable of opening as well as closing, most of thetime they are in the open site. They control the flow of ions during the restingmembrane potential. Examples include nongated Na+ and K+ channels that contribute tothe resting membrane potential. Gated Channels: These channels are also capable of opening as well as closing. All gated channelsare allosteric proteins The channels that are opened or closed by a change in the membrane potential arecalled voltage-gated channels. The opening and closing of the channel is believed to bedue to the movement of the charged region of the channel back and forth through theelectrical field of the membrane. Voltage-gated channels exist in three states: (1) resting state (the channel is closed but can be activated) (2) active state (the channel is open), and (3) refractory state (the channel is inactivated). Changes in the electrical potential difference across the membrane provide theenergy for gating in these channels. Genes encoding for voltage-gated Na+, K+, and Ca2+channels belong to one family. These channels are described as follows. The voltage-gated Na+ channel is formed by a single long polypeptide (a string ofamino acids containing peptide bonds) that has four domains (I-IV). Each domain hassix hydrophobic alpha helices (S1aS6) that span back and forth within the cellmembrane. The four domains join together and form an aqueous pore of the channel.An additional hydrophobic region connects the S5 and S6 alpha helical segments,
forming a pore loop. The presence of this pore loop makes the channel more permeableto Na+ than to K+. The membrane-spanning S4 alpha helical segment is believed to bevoltage sensitive. At the resting membrane potential, the channel pore is closed. The S4segment undergoes a conformational change when the membrane potential changes(e.g., when the neuron is depolarized), the S4 segment is pushed away from the innerside of the membrane, and the channel gate opens, allowing an influx of Na + ions. Thereare some cases where Na+ permeability is blocked. Tetrodotoxin (TTX), a toxin isolatedfrom the ovaries of Japanese puffer fish, binds to the sodium channel on the outside andblocks the sodium permeability pore. Consequently, neurons are not able to generateaction potentials after the application of TTX. These channels are also blocked by localanesthetic drugs (e.g., lidocaine). The basic structure of the voltage-gated Ca2+ channel is similar to that of thevoltage-gated Na+ channel. Ca2+ ions enter the postsynaptic neurons through thesechannels and activate enzymes. Depolarization of presynaptic nerve terminals results inentry of Ca2+ ions into the terminal via these channels. An increase in the levels ofintracellular Ca2+ results in the release of transmitters from presynaptic nerve terminals.Different varieties of voltage-gated K+ channels have been identified, and they servedifferent functions. The general scheme describing the components of this channel issimilar to that of the voltage-gated Na+ channel, except that the voltage-gated K+channel consists of four polypeptides. It should be recalled that each polypeptidecontributing to the formation of a large protein molecule is called a subunit. Eachsubunit of a voltage-gated K+ channel consists of six alpha-helical membrane-spanningsegments (S1 a S6). A pore loop makes the channel more permeable to K + than to Na+.The S4 segment acts as an activation gate. The K+ channels are generally blocked bychemicals such as tetraethylammonium (TEA) or 4-aminopyridine. The ligand-gated channels are opened by noncovalent binding of chemicalsubstances with their receptors on the neuronal membrane. These chemical substancesinclude: (1) transmitters or hormones present in the extracellular fluid that bind to theirreceptors on the extracellular side of the channel and bring about a conformationalchange to open the channel (e.g., acetylcholine, Î³-aminobutyric acid [GABA], orglycine); and (2) an intracellular second messenger (e.g., cyclic adenosine monophosphate,which is activated by a transmitter such as norepinephrine). The second messenger canopen the channel (1) directly by binding to the channel and causing a conformationalchange or (2) indirectly by phosphorylating the channel protein in the presence of aprotein kinase and causing a conformational change; this effect on the channel isreversed by dephosphorylation catalyzed by a protein phosphatase. Genes encoding fortransmitter-gated channels (e.g., channels activated by acetylcholine, GABA, orglycine) and genes encoding for voltage-gated channels belong to different families.Mechanically gated channels open by a mechanical stimulus and include the channelsinvolved in producing generator potentials of stretch and touch receptors.23 – Spreading of membrane potentials. Length and time constant of themembrane. An action potential elicited at any one point on an excitable membrane usuallyexcites adjacent portions of the membrane, resulting in the propagation of the actionpotential.
A nerve fiber excited at its midportion-develop increased permeability to Na+.Positive electrical charges carried by the inward diffusing Na+ flow inside the fiberthrought depolarized membrane and then for several milimiters along the core of theaxon. These positive cgarges increase the voltage to above the thereshold. Thus thedepolarization process travels along the entire extent of the fiber and the transmission ofthis depolarization process is called nerve impulse. The action potential will travel inboth directions away from the stimulus until the entire membrane becomes depolarized. Once an action potential has been elicited at any point on the membtrane of anormal fiber, the depolarization process travels over the entire membrane if conditionsare right, or it does not travel at all if conditions are not right- this is called “all ornothing principle”, and it applies to all normal excitable tissues. Occasionally, the actionpotential reaches a point on the membrane at which it does not generate voltage tostimulate the next area of the membrane. When this occurs, the spread of depolarizationstops. Therefore, for continued propagation of an impulse , the ratio of action potentialto threshold for excitation must at all times be greater than 1 – safety factor forpropagation. Length-constant: measures the effectiveness of neuron in longitudinal signaltransduction. Rm λ= √ ------------------- (Ri + Ro ) SOFIA: lambda e igual a raiz quadrada de abrir parentesis Rm sobre abrirparentesis ( Ri + Ro ) Rm: is the resistance across the membrane Ri: resistance inside the membrane Ro: is the resistance outside the membrane The larger the length constant the bigger the effect of the action potential Long leght constant results in spatial summation Time constant: T= Rm . Cm R: resistance C: capacitance Long-time constant results in temporal summation 24 – Temporal summation of membrane potentials. Temporal summation: is an effect generated by a single neuron as a way ofachieving action potential. Summation occurs when the time constant is sufficientlylong and the frequency of rises in potential are high enough that a rise in potential
begins before a previous one ends. The amplitude of the previous potential at the pointwhere the second begins will algebraically summate, generating a potential that isoverall lager than the individual potentials. This allows the potential to reach thethereshold to generate the action potential. Thus successive postsynaptic potentials caused by discharges from a single pre-synaptic, if they occur rapidly enough, can summate in the same way that postsynapticpotentials may summate from widely distributed terminals over the surface of a neuron. The degree of temporal summation is directly proportional to time – constant;and it occurs when the second potential arrises before the 1st has decreased. Temporal summation is involved in vision. The inverse proportion of intensityand time, applies as long as the stimulus is no greater than 0.1 second. For example, at0.1 second, 130 quanta are absorbed, un any matter of provision, but when raised to 1second there is a lesser rate of summation, needing 230 quanta to compensate for thedecrease in intensity. The frequency of vision is function of frequency of flashes, so thelonger the stimulus, the better chance it can attain the number of quanta needed forvision. 25 – Conduction velocity of the action potential, its determiants. When a region of an unmyelinated axonal membrane is depolarized sufficientlyby a depolarizing stimulus (e.g., a synaptic potential in a neuron) to reach a threshold
potential, voltage-gated Na+ channels open, Na+ flows into the axoplasm, and an actionpotential is generated in that region of the axon. Some of the current generated by theaction potential spreads by electrotonic conduction (passive spread) to an adjacentregion of the axon. The passive spread of current occurs by movement of electrons, andmovement of Na+ ions is not required. At the adjacent region, the passive spread ofcurrent results in opening of voltage-gated Na+ channels, influx of Na+ into theaxoplasm, and generation of an action potential. In other words, the passive spread ofvoltage along the length of an axon results in an active regeneration process. The propagation of an action potential along the axon depends on the cableproperties of the axon. The larger the diameter of the axon, the lower the resistancethere is to the flow of current along its length. Therefore, the conduction velocity(propagation of action potential) along the length of the axon can be increased byincreasing its diameter. For example, the axons of stellate ganglion neurons in the squidare about 1 mm in diameter (1000 times larger than the axons of mammalian neurons).The conduction of action potential in these squid giant axons is faster than inmammalian axons. The squid needs these fast conducting axons for faster contraction ofthe mantle muscles that produce a jet propulsion effect needed for quick escape frompredators. In vertebrates, the conduction velocity is increased by myelination of axon. Amyelin sheath consists of about 1-mm lengths of as many as 300 concentric layers ofmembrane around a single axon. In the peripheral nervous system, myelin is formed bySchwann cells. In the central nervous system, oligodendrocytes form the myelin. Nodesof Ranvier (bare segments of the axonal membrane with a very high density of voltage-gated Na+ channels) are present in between the segments of the myelin sheath. Themyelinated segments of an axon are not excitable and have a high resistance to theleakage of current across them. On the other hand, passive spread of current cangenerate an intense current at the nodes of Ranvier due to the presence of a high densityof voltage-gated Na+ channels.When a depolarizing stimulus (e.g., a synaptic potential in a neuron) arrives at a node ofRanvier, Na+ channels open, there is an influx of Na+ ions, and an action potential isgenerated at that node. Some current generated by the action potential spreads passivelyto the next node of Ranvier, and depolarization of the membrane at this node results inthe generation of an action potential. By this time, Na+ channels at the preceding nodeare inactivated, K+ channels open, and repolarization occurs. Thus, the action potentialpropagates along a myelinated axon by saltatory conduction (i.e., the jumping of anaction potential from one node to another). Myelination of an axon has two advantages:(1) conduction is very rapid along an axon, and (2) there is a conservation of metabolicenergy because excitation is restricted to the nodal regions that are relatively small (0.5Âµm). Conduction is also influenced by temperature, a high temperature leads to ahigher conduction velocity We can also note that the spinocerebellar tract has highest conduction velocity. 26 – Electrical and chemical transmission at synapses. Types of Synaptic Transmission:
Two types of synaptic transmission electrical and chemical are recognized in thenervous system. It should be noted that the electrical synapses are relatively lesscommon than the chemical synapses in the mammalian nervous system.Electrical Transmission In electrical transmission between the nerve cells, the current generated by animpulse in one neuron spreads to another neuron through a pathway of low electricalresistance. Electrical synapses occur at gap junctions. In an electrical synapse, ionchannels connect the cytoplasm of the presynaptic and postsynaptic cells. In the adultmammalian central nervous system, electrical synapses are present where the activity ofneighboring neurons needs to be highly synchronized. For example, hormone-secretingneurons in mammalian hypothalamus are connected with electrical synapses so that theyfire almost simultaneously and secrete a burst of hormone into the circulation. At an electrical synapse, the current generated by voltage-gated channels at thepresynaptic neuron flows directly into the postsynaptic neuron. Therefore, transmissionat such a synapse is very rapid (<0.1 msec). At some synapses (e.g., in the giant motorsynapse of crayfish), the current can pass in one direction (from presynaptic topostsynaptic neuron) but not in the reverse direction. Such synapses are called rectifyingor unidirectional synapses. At other synapses, the current can pass equally well in bothdirections. Such synapses are called nonrectifying or bidirectional synapses. Mostelectrical synapses in mammalian nervous system are believed to be the nonrectifyingtype.Chemical Transmission: At chemical synapses, there is no continuity between the cytoplasm of thepresynaptic terminal and postsynaptic neuron. Instead, the cells are separated bysynaptic clefts, which are fluid-filled gaps (20-50 nm). The presynaptic andpostsynaptic membranes adhere to each other due to the presence of a matrix ofextracellular fibrous protein in the synaptic cleft. The presynaptic terminal containssynaptic vesicles that are filled with several thousand molecules of a specific chemicalsubstance, the neurotransmitter. Pyramid-like structures consisting of proteins arise from the intracellular side ofthe presynaptic terminal membrane and project into the cytoplasm of the presynapticterminal. These pyramids and the membranes associated with them are called activezones and are the specialized release sites in the presynaptic terminal. The vesiclescontaining the neurotransmitter are aggregated near the active zones. Mechanisms of Transmitter Release: An action potential depolarizes the presynaptic nerve terminal, voltage-gatedCa channels located in the presynaptic terminal membrane open, Ca2+ permeability 2+increases, and Ca2+ enters the terminal. These events cause the membrane of the27 – Excitatory and inhibitory neurotrasmitters.Neurotrasmitter: chemical substance that is synthesized in a neuron, released at asynapse following depolarization of the nerve terminal (usually dependent on influx of
calcium ions), which binds to receptors on the postsynaptic cell and/or presynaptic terminal to elicit a specific response. (1) the substance must be synthesized in the neuron, and the enzymes needed for its synthesis must be present in the neuron;Small Molecule it must be released in sufficient quantity to elicit a response from the (2) GaseousNeurotransmittersneuron or cell located in the effector Neurotransmitters postsynaptic Neuropeptides organ;Acetylcholine(3) mechanisms forOpioid peptides Nitric oxide neurotransmitter from the removal or inactivation of theExcitatory amino acids exist; and Î˛-endorphin, synaptic cleft must Glutamate (4) it should mimic the action of the endogenously released neurotransmitter Methionine- Aspartate administered exogenously at or near a synapse. when enkephalinInhibitory amino acids Leucine-enkephalin GABA Endomorphins Glycine Nociceptin Classes ofBiogenic amines Substance P Neurotrans- Catecholamines mitters Dopamine Norepinephrine Epinephrine Indoleamine In the CNS, a neuron is contantly bombarded by neurotrasmitters, each of which Serotonin (5- can generate or modify a synaptic potential.hydroxytryptamine, [5-HT]) Neurotrasmitters that move the membrane potential towars depolarization with Imidazole amine the resultant production of an action potential are known as excitatory neurotrasmitters. Histamine Neurotrasmitters that move the membrane away from depolarization by making Purines the resting membrane potential more negative, the membrane is hyperrepolariyed, are ATP known as inhibitory neurotrasmitters. Adenosine Because the postsynaptic response is actually elicited by the receptor rather than by the trasmitters, the postsynaptic receptor determines whether a given neurotransmitter will be excitatory or inhibitory. Some neurotrasmitters can have either effect, depending on the type of postsynaptic receptor present. Excitatory: Acetylcholine, glutamate, aspratate.. Inhibitory: Dopamine, adenosine, serotonin, histamine, GABA… Both: Epinepherine, norepinepherine, glycine Acetylcholine Neurotransmitter in both the peripheral nervous system (PNS) and central nervous system (CNS). Acetylcholine is one of many neurotransmitters in the autonomic nervous system (ANS) and the only neurotransmitter used in the somatic nervous system. It is also the neurotransmitter in all autonomic ganglia. In the peripheral nervous system, acetylcholine activates muscles, and is a major neurotransmitter in the autonomic nervous system. When acetylcholine binds to acetylcholine receptors on skeletal muscle fibers, it opens ligand gated sodium channels in the cell membrane. Sodium ions then enter the muscle cell, stimulating muscle contraction. Acetylcholine, while inducing contraction of skeletal muscles, instead
induces decreased contraction in cardiac muscle fibers. This distinction is attributed todifferences in receptor structure between skeletal and cardiac fibers. In the autonomic nervous system, acetylcholine is released in the following sites: • all pre- and post-ganglionic parasympathetic neurons • all preganglionic sympathetic neurons o preganglionic sympathetic fibers to suprarenal medulla, the modified sympathetic ganglion; on stimulation by acetylcholine, the suprarenal medulla releases epinephrine and norepinephrine • some postganglionic sympathetic fibers o sudomotor neurons to sweat glands. In the central nervous system, ACh has a variety of effects as aneuromodulator, e.g., for plasticity and excitability. Other effects are arousal andreward. Damage to the cholinergic system in the brain has been suggested to play a rolein the memory deficits associated with Alzheimers Disease.Types of acetylcholine receptors:• Nicotinic AChRs are ionotropic receptors permeable to sodium, potassium, and chloride ions. They are stimulated by nicotine and acetylcholine. They are of two main types, muscle type and neuronal type. The former can be selectively blocked by curare and the latter by hexamethonium. The main location of nicotinic AChRs is on muscle end plates, autonomic ganglia (both sympathetic and parasympathetic), and in the CNS.• Muscarinic receptors are metabotropic, and affect neurons over a longer time frame. They are stimulated by muscarine and acetylcholine, and blocked by atropine. Muscarinic receptors are found in both the central nervous system and the peripheral nervous system, in heart, lungs, upper GI tract and sweat glands. Glutamate: Some of the important physiological and clinical considerations relevant toglutamate are as follows. • Glutamate has been implicated as a transmitter in a variety of circuits in the brain. E.g. excitatory amino acids may be involved in learning and memory processes, as well as motor functions. Dopamine is a neurotransmitter occurring in a wide variety of animals. In thebrain, it functions as a neurotransmitter, activating the five types of dopamine receptors
— D1, D2, D3, D4 and D5, and their variants. Dopamine is produced in several areas ofthe brain, including the substantia nigra and the ventral tegmental area. Dopamine isalso a neurohormone released by the hypothalamus. Its main function as a hormone is toinhibit the release of prolactin from the anterior lobe of the pituitary. Epinepherine: when in the bloodstream, it rapidly prepares the body for actionin emergency situations. The hormone boosts the supply of oxygen and glucose to thebrain and muscles, while suppressing other non-emergency bodily processes. Itincreases heart rate and stroke volume, dilates the pupils, and constricts arterioles in theskin and gastrointestinal tract while dilating arterioles in skeletal muscles. It elevates theblood sugar level by increasing catabolism of glycogen to glucose in the liver, and at thesame time begins the breakdown of lipids in fat cells. Like some other stress hormones,epinephrine has a suppressive effect on the immune system. Epinephrines actions are mediated through adrenergic receptors. Epinephrine is anon-selective agonist of all adrenergic receptors. It activates α1, α2, β1, and β2 receptorsto different extents. Specific functions include: • It binds to α1 receptors of liver cells, which activate inositol-phospholipid signaling pathway, signaling the phosphorylation of glycogen synthase and phosphorylase kinase (inactivating and activating them, respectively), leading to the latter activating another enzyme—glycogen phosphorylase—which catalises breakdown of glycogen (glycogenolysis) so as to release glucose to the bloodstream. Simultaneously protein phosphatase-1 (PP1) is inactivated, as in the active state PP1 would reverse all the previous phosphorylations. • Epinephrine also activates β-adrenergic receptors of the liver and muscle cells, thereby activating the adenylate cyclase signaling pathway, which will in turn increase glycogenolysis. β2 receptors are found primarily in skeletal muscle blood vessels where they triggervasodilation. However, α-adrenergic receptors are found in most smooth muscles andsplanchnic vessels, and epinephrine triggers vasoconstriction in those vessels. Epinepherine is found in the spinal cord, hypothalamus, thalamus andperiaqueducts. Serotonin: Serotonin-containing cells in the raphe regions of the brainstem are believed toplay a role in descending pain-control systems. Other serotonin-containing neurons mayplay a role in mediating affective processes such as aggressive behavior and arousal.Serotonin synthesized in the pineal gland serves as a precursor for the synthesis ofmelatonin, which is a neurohormone involved in regulating sleep patterns. Serotonin isalso believed to play an important role in depression. Histamin: Histamine has been implicated as a transmitter in the regulation of food andwater intake, as well as in thermoregulation and autonomic functions.
GABA: • GABA is an inhibitory transmitter in many brain circuits. E.g, GABA is used as an inhibitory neurotransmitter by the Purkinje cells in the cerebellum. Alteration of GABAergic circuits has been implicated in neurological and psychiatric disorders like Huntingtons chorea, Parkinsons disease, senile dementi… • Therefore, dietary deficiency of vitamin B6 can lead to diminished GABA synthesis. In a disastrous series of infant deaths.. GABA content in the brain of these infants was reduced. Subsequently, there was a loss of synaptic inhibition that caused seizures and death. • Since epileptic seizures can be facilitated by lack of neuronal inhibition, increase in the inhibitory transmitter, GABA, is helpful in terminating them • Barbiturates act as agonists or modulators on postsynaptic GABA receptors and are used to treat epilepsy.28 – Excitatory and inhibitory postsynaptic potentials. Postsynaptic potentials are changes in the membrane potential of thepostsynaptic terminal of a chemical synapse. Postsynaptic potentials are gradedpotentials, and their function is to initiate or inhibit action potentials. They are causedby the presynaptic neuron releasing neurotransmitters from the terminal button at theend of an axon into the synaptic cleft. The neurotransmitters bind to receptors on thepostsynaptic terminal, which may be a neuron or a muscle cell in the case of aneuromuscular junction. These are collectively referred to as postsynaptic receptors,since they are on the membrane of the postsynaptic cell. Neurotransmitters bind to theirreceptors by having a particular shape or structure, somewhat like the way a key fitsinto certain locks. Postsynaptic potentials are subject to summation, spatially and/or temporally.Excitatory postsynaptic potential (EPSP) is a temporary depolarization ofpostsynaptic membrane potential caused by the flow of positively charged ions into thepostsynaptic cell as a result of opening of ligand-sensitive channels. A postsynapticpotential is defined as excitatory if it makes it easier for the neuron to fire an actionpotential. IPSPs are sometimes caused by an increase in positive charge outflow. Theflow of ions that causes an EPSP is an excitatory postsynaptic current (EPSC). Inhibitory postsynaptic postsynaptic potentials. An inhibitory postsynaptic potential (IPSP) is a synaptic potential thatdecreases the chance that a future action potential will occur in a postsynaptic neuron orα-motoneuron.. They can take place at all chemical synapses which utilize the secretion
of neurotransmitters to create cell to cell signaling. Inhibitory presynaptic neuronsrelease neurotransmitters which then bind to the postsynaptic receptors; this induces apostsynaptic conductance change as ion channels open or close. An electrical current isgenerated which changes the postsynaptic membrane potential to create a more negativepostsynaptic potential. Depolarization can also occur due to an IPSP if the reversepotential is between the resting threshold and the action potential threshold. Anotherway to look at inhibitory postsynaptic potentials is that they are also a chlorineconductance change in the neuronal cell because it decreases the driving force. In general, a postsynaptic potential is dependent on the type and combination ofreceptor channel, reverse potential of the postsynaptic potential, action potentialthreshold voltage, ionic permeability of the ion channel, as well as the concentrations ofthe ions in and out of the cell; this determines if it is excitatory or inhibitory. IPSPsalways want to keep the membrane potential more negative than the action potentialthreshold and can be seen as a “transient hyperpolarization” EPSPs and IPSPs competewith each other at numerous synapses of a neuron; this determines whether or not theaction potential at the presynaptic terminal will regenerate at the postsynapticmembrane. Some common neurotransmitters involved in IPSPs are GABA and glycine.29 – Describe structural arrangement of the neuromuscular junction and itsfunction.The neuromuscular junction: The skeletal muscle fibers are innervated by large,myelinated nerve fibers that originate from large motorneurons in the anterior horns ofthe spinal cord. Each nerve fiber, after entering the muscle belly, normally branches andstimulates from three to several hundred several skeletal muscle fibers. Each nereveendings makes a junction, neuromuscular junction, with the muscle fiber near itsmidpoint. The action potential initiated in the muscle fiber by the nerve signal travels inboth directions towards the muscle fiber ends. The nerve fibres forms a complex of branching nerve terminals that invaginateinto the surface os the muscle fiber but lie outside the muscle fiber plasma membrane.The entire structure is called the motor end plate. It is vovered by one or more Scwmanncells that insulate it from the surronfing fluids. In the junction between a single axon terminal and the muscle fiber membrane,the invaginated membrane is called the synaptic gutter or synaptic trough, and the spacebetween the terminal and the fiber membrane is called the synaptic space or synapticcleft. This space is 20 to 30 nanometers wide. At the bottom of the gutter are numeroussmaller folds of the muscle membrane called subneural clefts, which gratly increase thesurface area at which the synaptic transmitter can act. In the axon terminal are many mitochondria that supply ATP, the energy sourcethat is used for the synthesis of an excitatory transmitter acetylcholine. Theacetylcholine in turn excites the muscle fiber membrane. Acetylcholine is synthetized inthe cytoplasm of the terminal, about 300.000 of which are normally in the terminals of asingle end plate. In the synaptic space are large quantities of the enzymeacetylcholinesterase, which destroys acetylcholine a few milliseconds after it has beenreleased from the synaptic vesicles. When a nerve impulse reaches the neuromuscular junction, about 125 vesicles ofacetylcholine are released from the terminals into synaptic space.
On the inside surface of the neural membrane are linear dense bars. To each sideof each dense bar are protein particles that penetrate the neural membrane; these arevoltage-gated calcium channels. When an action potential spreads over the terminal,these channels open and allow calcium ions to diffuse from the synaptic space to theinterior of the nerve terminal. The calcium ions, in turn, are believed to exert anattractive influence on the acetylcholine vesicles, drawing them to the neural membraneadjacent to dense bars. The vesicles then fuse with the neural membrane and empty theiracetylcholine into the synaptic space by the process of exocytosis.Myastenia gravis and Lambert-Eaton syndrome. Myastenis gravis is a serious and sometimes fatal disease in which skeletalmuscles are weak. It is caused by the formation of circulatory antibodies to the muscletype of nicotinic acetylcholine receptors. These antibodies destroy some of the receptorsand bind others to neighbouring receptors triggering their removal by endocytosis. Drugs affecting transmission at neuromuscular junction: a) some drugs act on acetylcholine thus stimulating the muscle fiber, e.g. nicotine b) some drugs may block transmission e.g. muscle relaxant. c) some drugs stimulate neuromuscular junction by inactivation ach- acetylcholinesterase e.g. physostigmine30 – Presynaptic inhibition and posttetanic potentiation In addition to the inhibition caused by inhibitory synapses operating at theneuronal membranes which is called post-synaptic inhibition, another type of inhibitionoften ocuurs in the presynaptic terminals before the signals even reaches the synapse –pre-synaptic inhibition. Pre-synaptic inhibition is the phenomenon that occurs when a presynapticneuron exerts inhibitory influences through transmitters at an axo-axonic synapse withthe terminal in a postsynaptic neuron. In presynaptic inhibition, the inhibition is caused by discharge of inhibitorysynapses that lie on the presynaptic terminals nerve fibrils before their endingsterminate on the post-synaptic neuron. In most instances, the inhibitory transmitterreleased is GABA, this has the specific effect of opening ion channels, allowing CL- todiffuse into the terminal fibril. Therefore the action potential itself becomes greatly reduced, thus also reducingthe degree of excitation of the postsynaptic neuron. Presynaptic inhibition occurs in many of the sensory pathways in the nervoussystem. 3 mechanisms of presynaptic inhibition are seen:⇒ Activation of the presynaptic receptors increases Cl- conductance, and this has been shown to decrease the size of the action potentials rwaching the excitatory ending.⇒ This in turn reduces Ca++ entry and consequently the amount of excitatory transmitter released. Voltage-gated K+ channels are also opened and the resulting K+ also decreases Ca++ influx.⇒ Evidence for direct inhibition of transmitter release independent of Ca++ influx into the excitatory ending is evident.
Post-tetanic potentiation If we stimulate motor unit and correlate it with the srenght of muscle contraction we can observe the principles of frequency summation and tetanization. First, with a lower rate of stimulation (times per second) and then increasing the frequency there comes a point where each new contraction occurs before the preeciding one is over. As a result, the second contraction is added partially to the first, so that the total strength of contraction rises progressively with increasing frequency. When the frequency reaches a critical level, the successive contractions eventually become so rapid that they fuse together, and the whole muscle contraction appears to be completely smooth and continuos. This is called tetanization. At a slightly higher frequency, the strength of contraction reaches its maximum, so that any additional increase in frequency beyond that point has no further effect in increasing contractile force. This occurs because enough calcium ions are maintained in the muscle sarcoplasm, even between action potentials, so that full contractile state is sustained without allowing any relaxation between the action potentials. The tetanizing stimulation causes Ca++ to accumulate in the presynaptic neuronto such a degree that the intracellular binding sites that keep cytoplasm Ca++ low areoverwhelmed. Postetanic potentiation is opposite to habituation31 – Spontaneously active neurons: Many neurons do not maintain a steady resting potential but fire impulsesspontaneously. Two patterns often seen are: a) regular firing or “beating” b) grouped firing or “bursting” In spontaneously active neurons, resting Na+ conductance is high, the leakagecurrent depolarizes and the threshold is crossed, and an action potential is fired. a) In regular firing neurons: in these neurons the membrane potential is lessnegative due to their possession of high Na+ leak conductance and low K+ leakconductancy. As the membrane potential moves to a more positive value, the theresholdis crossed quickly. After an impulse, voltage K+ channels open and the membrane ishyperepolarized. There is then a return to the resting potential due to to Na+ leakage. b)In bursting neurons: these neurons have the same membrane channels as firing neurons, they regulate action potentials during a burst. In depolarization of an action potential, voltage-gated Ca++ channels are opened to allow Ca++. They are slow, voltage-gated channels allow Na+, Ca++ exchange. This slow depolarization predominate during the impulse generating phase of the burst cycle. K+ channels which are activated by Ca++ are responsible for hyperrepolarisation (calcium-gated K+ channel). In bursting neurons, the leakage is slow, voltage dependent depolarizing channels (Na+, Ca++) generate the burst in a action potential. During this phase, Ca++ enters the cell by the voltage dependent Ca++ channels and activates Ca++