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Neural Plasticity: Long-term Potentiation

Neural Plasticity: Long-term Potentiation. Lesson 15. Neural Plasticity. Nervous System is malleable learning occurs Structural changes at synapses Changes in synaptic efficiency Long-term potentiation Long-term depression LTP & LTD throughout brain Many different mechanisms ~.

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Neural Plasticity: Long-term Potentiation

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  1. Neural Plasticity:Long-term Potentiation Lesson 15

  2. Neural Plasticity • Nervous System is malleable • learning occurs • Structural changes at synapses • Changes in synaptic efficiency • Long-term potentiation • Long-term depression • LTP & LTD throughout brain • Many different mechanisms ~

  3. Neural Mechanism of Memory • Donald Hebb • Short-term Memory • Change in neural activity • not structural • temporary • Reverberatory Circuits - • cortical loops of activity ~

  4. Reverberating Loops • Maintains neural activity for a period • Activity decays ~

  5. Hebb’s Postulate • Long-Term Memory • required structural change in brain • relatively permanent • Hebb Synapse • use strengthens synaptic efficiency • concurrent activity required • pre- & postsynaptic neurons ~

  6. Long-term Potentiation • According to Hebb rule • use strengthens synaptic connection • Synaptic facilitation • Structural changes • Simultaneous activity • Experimentally produced • hippocampal slices • associative learning also ~

  7. Inducing LTP Stimulating electrode Record Presynapticneuron Postsynapticneuron

  8. Postsynaptic Potential • Single Stimulation (AP) • High frequency stimulation • Single stimulation + -70mv -

  9. Experimentally-induced LTP • Pattern Of Stimulation • Brief, high frequency stimulation • > 10 Hz (10 AP/sec) • LTP Duration • Hippocampal slices: 40 hours • Intact animals: Up to a year ~

  10. LTP & Associative Learning • Associative learning • Respondent & Operant learning • Strengthening of association • Strong link: US  Response (UR) • Weak link: CS  Response (CR) • Concurrent activity • CS, US  Response • LTP in CS (strengthened)~

  11. LTP: Associative • Before Learning • Stim S  AP in R • W1 or W2 no AP in R W1 W1 R S US S W2 W2

  12. LTP: Associative • Induction • Paired: S + W1 AP • LTP in W1 • Unpaired: W2 no AP W1 W1 R S US S W2 W2

  13. LTP: Associative • After LTP • W1 alone  AP in R • W2 alone  no AP in R W1 W1 R S US S W2 W2

  14. LTP: Molecular Mechanisms • Presynaptic & Postsynaptic changes • HC  Glutamate • excitatory • 2 postsynaptic receptor subtypes • AMPA  Na+ • NMDA  Ca++ • Glu ligand for both ~

  15. NMDA Receptor • N-methyl-D-aspartate • Glu binding opens channel? • required, but not sufficient • Membrane must be depolarized • before Glu binds ~

  16. Single Action Potential • Glu  AMPA • a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate • depolarization • Glu  NMDA • does not open • Mg++ blocks channel • Little Ca++ into postsynaptic cell • Followed by more APs ~

  17. Mg Ca++ Na+ G G G G AMPA NMDA

  18. Mg Ca++ Na+ G G G G AMPA NMDA

  19. Mg Ca++ Na+ G G G G AMPA NMDA

  20. Mg Ca++ Na+ G G G G AMPA NMDA

  21. Activation of NMDA-R • Ca++ channel • chemically-gated • voltage-gated • Mg++ blocks channel •  Ca++ influx  post-synaptic changes • strengthens synapse ~

  22. Ca2+-mediated Effects • Activation of protein kinases • Protein Kinase C (PKC) • Ca2+/calmodulin-dependent protein kinase (CaMKII) • Targets: AMPA-R & other signaling proteins • CaMKII important role • Block CaMKII  No LTP • Self-phosphorylation   LTP duration ~

  23. LTP: Postsynaptic Changes • Receptor synthesis • More synapses • Shape of dendritic spines • Nitric Oxide synthesis ~

  24. Before LTP Presynaptic Axon Terminal Dendritic Spine

  25. After LTP less Fodrin Less resistance Presynaptic Axon Terminal Dendritic Spine

  26. Nitric Oxide - NO • Retrograde messenger • Hi conc.  poisonous gas • Hi lipid solubility • storage? • Synthesis on demand • Ca++  NO synthase  NO • Increases NT synthesis in presynaptic neuron • more released during AP ~

  27. Glu cGMP NO NOS NO Ca++ G G G G Ca++

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