Psy397 Lecture 4

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lec 4 LTP

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Psy397 Lecture 4

  1. 1. Long-term Potentiation Ruxandra Luca
  2. 2. The Cellular and Molecular Basis of Cognition
  3. 3. From Sidney Harris
  4. 4. True or False? <ul><li>How complex memories are stored and recalled at the neural circuit level, is very well understood. </li></ul><ul><ul><li>False </li></ul></ul>
  5. 5. <ul><li>Learning and Memory is measured by observing behaviour </li></ul><ul><li>Cellular changes  specific changes in neurons  alters the nervous system  change in behaviour </li></ul><ul><li>Therefore learning and memory are a result of changes in behaviour and are therefore linked to changes in the cellular level </li></ul><ul><li>So what are the cellular changes? </li></ul>
  6. 6. Changes at the Cellular Level Bring About Synaptic Plasticity <ul><li>Synaptic plasticity : alterations of synaptic connections between neurons, which subserves learning and memory </li></ul><ul><li>Neuron to neuron communications are made possible by synapses </li></ul><ul><li>At the synapse, neurotransmitters are released in response to excitation of the presynaptic neuron, which then diffuses across the synaptic cleft, binding to receptors on the postsynaptic cell </li></ul>
  7. 7. “ Hebb’s Postulate”: When an axon of cell A … excites cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A’s efficiency as one of the cells firing B is increased. D.O. Hebb, The Organization of Behavior , 1949.
  8. 8. <ul><li>Memories are stored as alterations in the strength of synaptic connections between neurons in the CNS. </li></ul>
  9. 9. TVP Bliss, FRS The discovery of LTP
  10. 10. In vivo recording from the rabbit hippocampus
  11. 11. The Entorhinal/Hippocampal System Entorhinal Cortex Dentate Gyrus CA3 Ipsilateral CA1 Perforant Pathway Mossy Fiber Schaffer Collaterals Stratum Lacunosom Molecular inputs Recurrent Connections
  12. 12. Bliss and Lomo’s First Published LTP Experiment No tetanic stimulation Tetanic stimulation High frequency synaptic stimulation, resulting in LTP
  13. 13. The Entorhinal/Hippocampal System Lateral Septum, Contralateral CA1 Entorhinal Cortex Dentate Gyrus CA3 Ipsilateral CA1 Perforant Pathway Mossy Fiber Entorhinal Cortex Subiculum Lateral Septum Amygdala, Cortex Schaffer Collaterals Norepinephrine, Acetylcholine, Serotonin GABAergic Interneuron CA1 Axon Schaffer Collaterals Stratum Lacunosom Molecular inputs Recurrent Connections SLM Inputs Dopamine,
  14. 14. The Dendritic Tree with a single axon passing through
  15. 15. The Dendritic Spines: thousands of contact points (synapses)
  16. 16. View of pre- & post-synaptic terminals DS = dendritic spine Sp = Synapse (postsynaptic terminal) AT = Axon (pre-synaptic) terminal Arrows indicate synaptic density
  17. 17. The Entorhinal/Hippocampal System Lateral Septum, Contralateral CA1 Entorhinal Cortex Dentate Gyrus CA3 Ipsilateral CA1 Perforant Pathway Mossy Fiber Entorhinal Cortex Subiculum Lateral Septum Amygdala, Cortex Schaffer Collaterals Norepinephrine, Acetylcholine, Serotonin GABAergic Interneuron CA1 Axon Schaffer Collaterals Stratum Lacunosom Molecular inputs Recurrent Connections SLM Inputs Dopamine,
  18. 18. Stimulating Electrode Recording Electrode Electrodes in a Living Hippocampal Slice
  19. 19. Tissue Slice Chamber
  20. 20. Stimulating Schaffer Collaterals in Area CA3 Recording in Stratum Pyramidale in Area CA1 Recording in Stratum Radiatum in Area CA1 Stimulus Artifact Fiber Volley EPSP Recording Configuration and Typical Responses in a Hippocampal Slice Recording Experiment Cell body layer Dendritic regions
  21. 21. B A An Input/Output Curve and a Typical LTP Experiment Delivery of 100 Hz synaptic stimulation
  22. 22. <ul><li>Can synapses reach a maximum synaptic strength if potentiation is very long-lasting? </li></ul><ul><li>What happens then? </li></ul><ul><li> elimination of synaptic plasticity </li></ul><ul><li>But LTP is not irreversible and every synapse will not potentiate with time </li></ul>
  23. 23. From Nicoll et al.
  24. 24. Malenka et al, Bear et al, Huganir et al. Low frequency stimulation induces Long-Term Depression (LTD)
  25. 25. Theta Pattern in Hippocampal EEG 1-voluntary movement 2-REM sleep 3-still-alert 4-slow-wave sleep Before and after a medial septal lesion.
  26. 26. LTP Triggered by Theta Burst Stimulation … 100-Hz 100-Hz 100-Hz 100-Hz 200 msec 200 msec 200 msec 10 msec between pulses <ul><li>5-Hz burst frequency </li></ul><ul><li>10 bursts per train </li></ul><ul><li>3 trains, 20-sec intertrain interval </li></ul>A B Time (min) fEPSP slope (% of baseline) -20 0 20 40 60 75 100 125 150 175 200
  27. 27. Voltage Clamp Cell Body Stimulating and recording from a single neuron: pairing two stimuli Axon
  28. 28. Pairing two stimuli : Postsynaptic depolarization + presynaptic elctric pulse leads to LTP
  29. 29. What Purpose does Pairing LTP Serve? <ul><li>It functions as a coincidence detector </li></ul><ul><li>When there is presynaptic and postsynaptic activity, the neuron can trigger a unique event </li></ul><ul><li>Associatively property arises out of this pairing </li></ul><ul><li>For instance, low-frequency synaptic activity with postsynaptic depolarization can actually lead to LTP </li></ul>
  30. 30. Gly Glu + + + + - - - - - - - + + + Synaptic Glutamate Alone Cytoplasm Synaptic Cleft Mg ++ Ca ++ Glu Ca ++ + + + + - - - - Mg ++ Gly - - - + + + Glutamate plus Membrane Depolarization Cytoplasm Synaptic Cleft Ca ++ The NMDA Receptor is a coincidence detector
  31. 31. Experimental set up for the analysis of the associative nature of LTP
  32. 32. ASSOCIATIVE NATURE OF LTP German Barrionuevo and Tom Brown
  33. 33. Back Propagating Action Potential: From soma to dendrite stimulation recording recording Action potential K+ current
  34. 34. When postsynaptic depolarization precedes presynaptic neurotransmitter release synaptic depression occurs.
  35. 35. Pairing LTP TTX = tetrodotoxin (Na+ channel blocker inhibiting dendritic action potential)
  36. 36. NEURONAL INFORMATION PROCESSING
  37. 37. MOLECULAR MECHANISMS Graham Collingridge NMDA APV = AP5 (NMDA-R antagonist)
  38. 38. APV blocks LTP induction APV Time (min) fEPSP slope (% of baseline)
  39. 39. EPSP’s Synaptic Activity NE, Ach, S receptors Change in Local excitability 1 2 Synapse LTP? A B The Dendritic Tree and Regulation of Action Potential Propagation
  40. 40. NMDAR Independent LTP 200 Hz Mossy Fiber Tetra-ethyl ammonium (K+ channel blocker) induced LTP
  41. 42. Question <ul><li>Theoretically, would an agent that blocks potassium channels be able to induce LTP? </li></ul><ul><ul><li>Yes. If it increases membrane excitability, there is an increased chance that it will </li></ul></ul><ul><ul><li>For instance TEA+ (tetraethylammonium) ion application </li></ul></ul>
  42. 43. PTP PPF Other forms of synaptic plasticity: pre-pulse facilitation and post-tetanic potentiation
  43. 44. Synaptic strengthening: changes that may underlie LTP
  44. 48. <ul><li>LTP= long-lasting change in output in response to transient input= learning </li></ul>

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