Neurophysiology in ped neurology

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  • the body. Scientists estimate conservatively that there aremore than 100 billion neurons in the brain and about 1 billion neurons in the spinal cord+ glia all around
  • Most cells in the body have geometric shapes—they are squarish, cubical, or spherical. Pyramidal tract is an exampleA single neuron can have anywhere from 1 to 20 dendrites, each of which can branch many times. Dendrites receive messages from other neurons and carry them toward the cell body.
  • Soma= neuron stimuli to neuron forReceives information and Integrates informationElectrical signal= action potentialsCONNECTIONSThe nervous system is an intricate network of neurons (nervecells) and their connections. Surrounding the neurons areglia, which play many supportive roles in the nervous system.Neurons receive and process chemical messages fromother neurons and then send electrical signals down theiraxons to trigger the release of neurotransmitters—chemicalmessengers—that go out to other neurons. The electricalcurrent that travels down the neuronal axon is made up of aseries of action potentials, which are generated by the openingof voltage-gated Na+ channels in the axon membrane.
  • Glia are special cells that play a supporting role in the nervous system. They outnumber neurons by about 10 to 1 in the brain, where they make up at least half of the brain’s volume. The number of glia in other parts of the nervous system has not yet been determined. Unlike neurons, glia are replaced constantly throughout life. Like neurons, glia have many extensions coming off their cell bodies. Unlike neurons, however, most glia do not transmit electrical impulses. A recent discovery—that a subtype of oligodendrocyte precursor cells (OPSs) generate electrical signals—challenges the traditional view that no glial cells can do so. These special glial cells notonly generate electrical impulses but also receive input from neuronal axons.
  • 1-Astrocytes surround neurons and provide structural support to hold neurons in place. 2-They provide nutritional support by contacting nearby blood vessels and transporting glucose and other nutrients from the bloodstream.3- uptake of neurotransmitters from the synapse, regulation ofthe extracellular potassium (K+) concentration, 4- synthesis and release of nerve growth factors (that help repair damaged nerves outside the brain and spinal cord.5-the scavenging of deadcellsafter an injury to the brain.
  • THE BLOOD-BRAIN BARRIERAstrocytes also contribute to the formation of the blood-brainbarrier. Processes from astrocytes called “end feet” adhere to theblood vessels of the brain and secrete chemical signals that induce(cause) the formation of tight junctions between the endothelialcells that line the blood vessels. As a result, substances from theextracellular fluid cannot move easily into these cells. The smallpores called fenestrations and some of the transport mechanismsthat are present in peripheral blood vessels are absent in the membranesof the cells that line the brain’s blood vessels.The blood-brain barrier keeps most substances other thanoxygen, glucose, and essential amino acids from entering the brainfrom the bloodstream. It protects the brain from toxins, peripheralneurotransmitters, and other substances that would interfere withthe brain’s functioning. Most large molecules cannot cross this bloodbrainbarrier. Small fat-soluble molecules and uncharged particlessuch as carbon dioxide and oxygen, however, diffuse easily across thisbarrier. Glucose and essential amino acids are transported across byspecial transporter proteins. Toxins that can diffuse across the bloodbrainbarrier include nerve gases, alcohol, and nicotine
  • Oligodendrocytes are found in the brain and spinal cord,whereas Schwann cells are found in the peripheral nervoussystem. Both cell types have fewer extensions than astrocytes.Their main function is to provide the myelin sheath that coversmyelinated axons. Like astrocytes, they also help bringnutritional support to neurons. Schwann cells secrete growthfactors that help repair damaged nerves outside the brain andspinal cord.Myelin is the covering of glial extensions that wrap aroundthe axon of a neuron in as many as 100 layers. Each oligodendrocytemay wrap a different process around one segment ofthe axon of up to 50 different neurons. In the nerves outsidethe brain and spinal cord, Schwann cell processes wrap around
  • Saltatory: combines both types of currentspeed without loss of signal Current passes through a myelinated axon only at the nodes of Ranvier. Voltage-gated Na+ channels are concentrated at these nodesAction potentials are triggered only at the nodes and jump from one node to the next . Much faster than conduction along unmyelinated axons
  • Myelin is the covering of glial extensions that wrap around the axon of a neuron in as many as 100 layers. Each oligodendrocyte may wrap a different process around one segment of the axon of up to 50 different neurons. In the nerves outside the brain and spinal cord, Schwann cell processes wrap around one short segment of the axon of just one neuron. The layers of myelin provide additional electrical insulation that helps the nerve signal travel faster and farther
  • Ependymal cells are glial cells that line the ventricles, thefluid-filled cavities of the brain. Unlike other glial cells, they donot have processes coming off the cell body. They secrete cerebrospinalfluid, the liquid that fills the ventricles and the spinalcanal. Cerebrospinal fluid acts as a shock-absorbing cushionto protect the brain from blows to the head. In effect, this fluidmakes the brain float inside the skull. The cerebrospinal fluidalso removes waste products from the brain.
  • Small cells called microglia migrate from the blood intothe brain. They act as the cleanup crew when nerve cells die.They also produce chemicals called growth factors that helpdamaged neurons to heal. When you view a damaged area ofthe brain under a microscope, you can see glial cells clusteredin the places where dead cells were removed.
  • May add a more lipid from myelin sheath
  • Phospholipids arethe most common lipid found in the cell membrane.
  • Becausethe phosphate-containing “head” of a phospholipid moleculeis attracted to water (hydrophilic) and the fatty acid-containing “tail” is repelled by water (hydrophobic), the phospholipid molecules spontaneously form a bilayer with the fatty acid tails in the middle (Figure 1.4). This bilayer forms a barrier between the water outside the cell and the water inside the cell. It also keeps substances that are dissolved in water, such as ions, from crossing the cell membrane. Very few substances other than gases can cross the lipid bilayer easily.
  • Some channels areopen all the time to let particular ions move back and forth.These channels are said to be ungated.
  • Between the tip of each axon terminal and the point on the target neuron (usually a dendritic spine or the cell body) to which the axon sends a nerve signal, there is a tiny gap. It measures about 10 to 20 nanometers (3.94 to 7.87 in) across and iscalled the synaptic cleft.
  • The synapse is the junction of a neuron with anotherneuron or a muscle fiber..Neurotransmitters carry the nerve signal as a chemical messageacross the synaptic cleft from the first (presynaptic) neuron to thesecond (postsynaptic) neuron. The neurotransmitter molecules bind toreceptors in the membrane of the postsynaptic neuron
  • Few ions and molecules besides water and small unchargedmolecules, such as oxygen and carbon dioxide, can easily pass throughthe lipid bilayer of the cell membrane. Other substances needed forcell function must cross the cell membrane through special transporterproteins that span the lipid bilayer. These transporter proteins are highlyselective, allowing only a particular ion or molecule to pass.
  • On presynaptic terminal. Binds NTsame as postsynaptic receptors different receptor subtypeDecreases NT release & synthesis Metabotropic receptor :alters protein synthesis ~
  • ION PUMPS AS NA AND K PUMP
  • ligand-gated
  • specialmembrane protein, known as the sodium-potassium pump,helps control the Na+ and K+ concentrations by using energyto pump three Na+ ions out for every two K+ ions it allowsin. The area just inside of the plasma membrane is about 70millivolts, or mV (a millivolt is one thousandth of a volt),more negative than that of the extracellular fluid just outsidethe cell membrane. This electrical charge is called the restingpotential of the membrane. The interior of the cell membraneis said to be “polarized.”
  • * And GABA release
  • Neurophysiology in ped neurology

    1. 1. IF THE HUMAN BRAINWERE SO SIMPLE THAT WECOULD UNDERSTAND IT,WE WOULD BE SO SIMPLETHAT WE COULDN’T.
    2. 2. Synapsis /Transmittors
    3. 3. Neuron The basic signaling unit of the nervous system is the neuron. Neurons are found in the brain, spinal cord, and throughout the body Neurons come in many shapes and sizes and perform many different functions.
    4. 4. Shorthand for neuron
    5. 5. NEURONS Basic functional unit of N.S. Specialized cell  All cells have same basic properties information processing Transmits Integrates Stores Regulation of behavior ~
    6. 6. By morphologyMultipolar Bipolar Pseudo-Unipolar axon Cell 20 body1 Dendritic tree
    7. 7. 3 Functional types of neurons sensory motor - + + + + interneuron + sensory
    8. 8.  ~Stimuli  Axon carries information away from soma  Electrical signal  Axon terminal releases chemical message~
    9. 9. GliaNeural Support Cells 10X100 billions Replaced all life
    10. 10. Four main types of glial cells Astrocytes Myelin producing oligodendrocytes and Schwann cells Ependymal cells Microglia.
    11. 11. 1- Astrocytes Provide physical support/ nutrition Regulating chemical content of ECF NTs & G K+ concentration N growth factors: synthesis & release the scavenging of dead cells after an injury to the brain. BBB role
    12. 12. Blood-Brain Barrier Astrocyte roleTypical end feetCapillary fenestrations Brain Capillary
    13. 13. Glucose transport BBB
    14. 14. THE BLOOD-BRAIN BARRIER BBB: Astrocyte Function  Maintains stable brain environment large fluctuations in periphery  Barrier to poisons  Retains neurotransmtters & other chemicals  Regulates nutrient supplies glucose, AA levels: active transport
    15. 15. 2-oligodendroglia / Schwann cells Myelin plus Wrap around axon  Bring nutrition Saltatory Conduction support  faster transmission  Nerve Growth factor
    16. 16. Saltatory Conduction Figure 11.16
    17. 17. Saltatory transission
    18. 18. Myelin Brain/spinal cord: Oligodendrocyte Peripheral nerves: Schwann cell Function: Nerve signal travel faster and faster
    19. 19. 3- Ependymal cells line walls of ventricles role in neuron cell migration during development
    20. 20.  CSF production: Origin: mainly from the choroid plexus in the lateral, third and fourth ventricles. Process: an active process with sodium is pumped out then water Rate of production: 20 ml /hour Normal CSF volume: 50 cc in infancy and 150 cc in adult
    21. 21. CSFMOVEMENTCSF movements aredue to hydrostaticgradient between theventricular system(about 120 mmH2O)and venouschannel(about90mmH2O).
    22. 22. *Average volume: Intracranial C.S.F 125ml Subarachnoid space 89 ml Lumbar sac 30 ml *Normal C.S.F Pressure Infants 40-50 mm H2O Children 40-100 mm H2O Older age 150 mm H2O >200 mm H2O is abnormalC.S.F pressure is about 40-50 mm H2O above intracranial venous pressure. C.S.F pressure falls with inspiration and rises With expiration
    23. 23. When does Hydrocephalus appear ? 1- When there is over production of CSF. 2- When there is a blocking in the paths of the CSF circulation. 3- When not all the CSF produced is "eliminated".
    24. 24. 4- Microglia Microglia  Phagocytosis of dead nerve cells #  Produce nerve growth factors
    25. 25. THE PLASMA MEMBRANEAND THE MEMBRANE POTENTIAL The plasma membrane of neurons is made up of a lipid bilayer, a double layer of fatty molecules.
    26. 26. Phospholipids <------- Phosphate head hydrophilic <------- Lipid tails hydrophobic
    27. 27. Phospholipid Bilayer water plusHydrophilic heads ----->Hydrophobic tails ----->
    28. 28. Ungated channels: H20 out & in H 2O H 2O
    29. 29. SynapticTransmission
    30. 30. How does a nerve signaltravel from one neuron to another?
    31. 31. Synaptic Cleft the synaptic cleft.
    32. 32. Synapse
    33. 33. Post synaptic Receptors
    34. 34. Presynaptic PostsynapticAxon Terminal Membrane the synaptic cleft. Terminal Button Dendritic Spine
    35. 35. 1. Precursor Transport
    36. 36. 2. Synthesisenzymes/cofactors _ _ _ NT
    37. 37. 3. Storagein vesicles
    38. 38. NT Terminal Button Dendritic Spine SynapseVesicles
    39. 39. 4. Release Terminal Button Dendritic Spine Synapse Receptors
    40. 40. Terminal Button Dendritic SpineAP Synapse
    41. 41. ExocytosisCa++
    42. 42. 5. Activation
    43. 43. 6. Termination
    44. 44. 6. Termination by... Diffusion
    45. 45. 6. Termination by...Enzymatic degradation
    46. 46. 6. Termination by... Reuptake
    47. 47. 6. Termination by... Autoreceptors A
    48. 48. Membrane Proteins Channels Pumps  active transport Receptor protein sites  bind messenger molecules Transducer proteins:  2d messenger systems Structural proteins  form junctions with other neurons ~
    49. 49. Membrane Proteins 3 3 Na GATED OUTSIDE INSIDE NON GATED 2K
    50. 50. Membrane Proteins: Ionophores  Ions Channels  Nongated always open  Gated chemically-gated electrically-gated mechanically-gated ~
    51. 51. Chemically-Gated Channels Ionotropic direct control ---> fast Metabotropic second messenger system indirect ---> slow ~
    52. 52. Ionotropic ChannelsChannel NT neurotransmitter
    53. 53. Ionotropic Channels NTRAPID Pore
    54. 54. Ionotropic Channels NT
    55. 55. Ionotropic Channels
    56. 56. Metabotropic Channels Receptor separate from channel 2d messenger system  G proteins  cAMP  other types Effects  Control channel  Alter properties of receptors  regulation of gene expression ~
    57. 57. G protein: direct control NT is 1st messenger G protein binds to channel  opens or closes  relatively fast ~
    58. 58. G protein: direct control R G GDP
    59. 59. G protein: direct control R G GTP Pore
    60. 60. G protein: Protein Phosphorylation Open or close channels at resting Vm NT = 1st messenger Membrane-associated components  Receptor  Transducer  Primary effector Intracellular  2d messenger  Secondary effector ~
    61. 61. G protein: Protein Phosphorylation external signal: nt norepinephrine Receptor b adrenergic -R trans- primary adenylyl GS ducer effector cyclase 2d messenger cAMP secondary effector protein kinase
    62. 62. G protein: Protein Phosphorylation A C R G GDP PK
    63. 63. G protein: Protein Phosphorylation A C R G ATP GTP cAMP PK
    64. 64. G protein: Protein Phosphorylation A C R G ATP GTP P cAMP PK Pore
    65. 65. Resting membrane potential 3 - Ca++ -70 mV 2
    66. 66. Inside Outside Na+Na+ Na+ + K+ K+ -VE 70 MV ATP
    67. 67. Inside Outside K+ K+
    68. 68. Action Potential
    69. 69. Na Channels Essential for depolarization during action potential Blocking fast channel inactivation leads to increased excitability  Induces paroxysmal depolarization shifts  Increasing synchrony
    70. 70. +40 C & E gradients drive Na+ into cell 0 Depolarization Na+ influx-60-70-80 Time
    71. 71. outside Na+posnegaxon K+ DEPOLARIZATION
    72. 72. outside Na+ Na+neg Na+pos Na+ Na+ Na+axon K+ DEPOLARIZATION
    73. 73. +40 Amplitude = 110 mV 0 Depolarization - 70 mV to +40 mV Na+ influx-60-70-80 Time
    74. 74. K Channels Important for post-excitatory membrane re-polarization M current controls sub-threshold membrane excitability K Channel blockade produces epileptiform discharges in vitro M current defect identified in benign neonatal familial convulsions
    75. 75. outside Na+ Na+neg Na+pos Na+ Na+ Na+axon K+ REPOLARIZATION
    76. 76. outside Na+ K+ Na+ K+pos K+ K+ K+neg Na+ Na+ Na+ K+axon K+ REPOLARIZATION
    77. 77. outside Na+ K+ K+ K+ K+pos K+ K+ K+ K+neg Na+ Na+ Na+ K+axon K+AFTER-HYPERPOLARIZATION
    78. 78. +40 0 Repolarization K+ efflux-60-70-80 Time
    79. 79. +40 0 After- hyperpolarization-60-70-80 Time
    80. 80. Ca Channels Different types of channels (T, N, L, P, Q) Ca currents contribute to the paroxysmal depolarization shift May be responsible for long-term structural changes affecting excitability and synaptic efficacy Participate in cytotoxicity Activation of T-type channels is thought to underlie the abnormal thalamocortical rhythmicity associated with 3-Hz spike- and-wave in absence
    81. 81. Synaptic Events Action Potential reaches axon terminal Chemical substance released Neurotransmitter (NT) Diffuses across synapse Binds to receptor protein EPSP or IPSP ~
    82. 82. Neurotransmitters Lecture
    83. 83. CRITERIA NT found in axon terminals NT released by action potentials
    84. 84. Lock & Key Model NT binds to receptor NT = key Receptor = lock Receptor changes shape determines if EPSP or IPSP receptor subtypes
    85. 85.  ligand binds to receptor activation: + or - NT Receptor A
    86. 86.  Same NT can bind to different -R by different part of NT NT Receptor A Receptor B
    87. 87. Specificity of drugs Drug B Drug A NT Receptor A Receptor B
    88. 88. Seizures and Epilepsy
    89. 89. Mechanisms of Seizures Defective balance between excitatory and inhibitory neurotransmission + - +VE -VE
    90. 90. What causes neuronal hyperexcitability? +VE  Changes in Excitatory receptors Excitatory amino acid receptors Enhancement: NMDA, AMPAChanges in ion channels  Excitatory AA : Glutamate, aspartate
    91. 91. Na K Ca
    92. 92. Excitatory amino acid (EAA) receptors EAA: glutamate and aspartate Two main receptor types: AMPA/kainat e and NMDA
    93. 93. NMDA receptor Sustains long- lasting depolarization events NMDA agonists induce epilepsies in animals Structural changes have been seen in surgical specimens Involved in long term potentiation
    94. 94. GABA receptors Activation leads to membrane hyperpolarizati on via inflow of Cl and outflow K Decreased neuronal firing
    95. 95. the synaptic cleft.
    96. 96. Gamma-aminobutyric acid GABA - GABAergic Major NT in brain inhibitory system Receptor subtypes GABAA - controls Cl- channel GABAB - controls K+ channel Precursor = glutamate ~
    97. 97. What causes neuronal hyperexcitability? -VE  Changes in Inhibitory receptors GABA – A receptors  inhibitory AA : Plus GABAChanges in ion channels
    98. 98. GABA receptors There are two classes of GABA receptors: GABAA and GABAB.
    99. 99. GABA receptors Activation leads to membrane hyperpolarization via inflow of Cl and outflow K Decreased neuronal firing
    100. 100. GABA GABA is one of the main inhibitory NTs in the brain. GABAergic neuron dysfunctions lead to seizures
    101. 101. GABA Synthesis glutamic acid decarboxylaseGlutamate GABA
    102. 102. GABA Synthesis & Reuptake From Krebs cycle metabolism of glucose in mitochondria From Glial cells GABA ---> Glutamate ---> Glutamine Glutamine into neurons After release GABA back into glia ~
    103. 103. LEVETIRACETAM FIRST OF A NEW CLASS OF AEDSLynch, PNAS 2004 For internal use only
    104. 104. What causes neuronal hyperexcitability? Changes in ion channels 1- Na ions channels 2- K ions channels 3- ca ions channels
    105. 105. Na Channels Essential for depolarization during action potential Blocking fast channel inactivation leads to increased excitability  Induces paroxysmal depolarization shifts  Increasing synchrony
    106. 106. Ca Channels Ca currents contribute to the paroxysmal depolarization shift Activation of T-type channels is thought to underlie the abnormal thalamocortical rhythmicity associated with 3-Hz spike- and-wave in absence (absence seizures) Different types of channels (T, N, L, P, Q)
    107. 107. K Channels Important for post-excitatory membrane re-polarization K Channel blockade produces epileptiform discharges in vitro
    108. 108. AED
    109. 109. AED Modes of action1 Suppress action potential Sodium channel blocker or modulator Potassium channel opener* Ca channels and transmitter release 118
    110. 110. Modes of action2 Enhance GABA transmission GABA uptake inhibitor GABA mimetics3 Suppression of excitatory transmission 4- SVA inhibitor 119
    111. 111. Sodium channels Main target for many drugs Sodium channels are responsible for the rising phase of the action potential in excitable cells and membranes Examples: Phenytoin Carbamazepine Oxcarbazepine 120 Lamotrigine
    112. 112. Potassium channels Very diverse group of ion channels Responsible for resting potential Influences excitability of neurones Determine potential width 121
    113. 113. Calcium channels T type  Ethosuximide, zonisamide L type  Barbiturates, felbamate N type  Lamotrigine, barbiturates , oxcarbazepine P/Q type 122  Lamotrigine, oxcarbazepine
    114. 114. Calcium channels Four main types  L, P/G, N; high voltage  T; low voltage Mono amines modulate the circuit Nifedipine blocks L 123
    115. 115. GABA A and GABA B Inhibitory neurotransmitter GABA A post synaptic; 7 classes  Dependent upon chloride and bicarbonate ions GABA B pre and post synaptic 124
    116. 116. GABA A Transmission Barbiturates (+ open Cl channels)  primidone Benzodiazepines (GABA mimic)  Clobazam, clonazepam, diazapam Tiagabine Vigabatrin VPA ( decrease its uptake) 125
    117. 117. Glutamate Major excitatory transmitter  Mainly intracellular Three receptor types  NMDA Associated with sodium and calcium ions Magnesium ions block Other messengers act at NMDA site  AMPA and kainate receptors 126  metabotropic
    118. 118. Other Mechanisms Levetiracetam 127
    119. 119. Other (unique) LEVETIRACETAMLynch, PNAS 2004 For internal use only
    120. 120. Sites of action Valproate, vigabatrin, tiagabine increase GABA by inhibiting reuptake and preventing breakdown within the cell Benzodiazepines bind to GABA receptors Phenobarbital opens chloride channels Topiramate blocks sodium channels 129 and is a GABA agonist at some sites
    121. 121. 130
    122. 122. Other modes of action Gabapentin, has similar structure to GABA Phenytoin,carbamazepine,oxcarbazepin e, lamotrigine, act on sodium channels Ethosuximide, reduces calcium currents Levetiracetam, has neuroprotective effect Topiramate, acetazolamide, are carbonic anhydrase inhibitors Zonisamide has weak carbonic 131 anhydrase activity
    123. 123. Thank you 132
    124. 124. 1- GABA(A) receptor agonisti)Barbiturates:Barbexaclone · Metharbital · Methylphenob arbital· Pentobarbital · Phenobarbital. Primidoneii)Benzodiazepines: Clobazam · Clonazepam · Clorazepate ·Diazepam# · Flutoprazepam · Lorazepam ·Midazolam · Nimetazepam · Nitrazepam · 133Temazepam
    125. 125. 2- OTHER GABA agentsAromaticallylic alcohols (Stiripentol) 134
    126. 126. 3- Carbonic anhydrase inhibitor:Sulfa drugs Acetazolamide · Ethoxzolamide · Sult iame ·Zonisamide 135
    127. 127. 4- Channel blockers1)Primarily sodium:#Hydantoins:Ethotoin · Fosphenytoin · Mephenytoin · Phenytoin#Carboxamides: Carbamazepine# · Eslicarbazepine acetate · Oxcarbazepine ·Rufinamide2)Primarily calcium#Succinimides:Ethosuximide# · Mesuximide · Phensuximide3)Unknown/ungrouped:#Phenyltriazines: Lamotrigine#Oxazolidinediones:Ethadione · Paramethadione · Trimethadione Ureas Phenacemide · Pheneturide#MonosaccharidesTopiramate 136
    128. 128. 5- Indirect GABA agents Carboxylic acids/ Fatty acid derivativesi)GABA transaminase inhibitor:Valproic acid# (Sodium valproate & Valproate semisodium) · Valpromide · Valnoctamideii)GABA reuptake inhibitor: Tiagabine GABA analogs · Gabapentin Pregabalin· Progabide · Vigabatrin 137
    129. 129. 6- Unknown/multiple/ unsortedi)Carbamates: Emylcamate · Felbamate · Meprobam ate · Carisbamateii)Pyrrolidines:Brivaracetam · Levetirac etam · Nefiracetam · Seletracetamiii)Propionates:Beclamide · Lacosamid eiv)Aldehydes: Paraldehyde 138v)Bromides: Potassium bromide · Sodium bromide
    130. 130. inhibitors excitatory1- GABA2 1- Ca + channels2- enhanced GABA level 2- Na + channels 1393- K+ channels 3- glutamate

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