1. Neural Plasticity: Long-term Potentiation Lesson 15

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

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

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

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

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

7. Inducing LTP Stimulating electrode Record Presynaptic neuron Postsynaptic neuron

8. -70mv - + Postsynaptic Potential 1. Single Stimulation (AP) 2. High frequency stimulation 3. Single stimulation

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

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

11. W1W1 W2W2 S R W1W1 W2W2 S US LTP: Associative n Before Learning l Stim S  AP in R l W 1 or W 2  no AP in R

12. W1W1 W2W2 S R W1W1 W2W2 S US LTP: Associative n Induction l Paired: S + W 1  AP LTP in W 1 l Unpaired: W 2  no AP

13. W1W1 W2W2 S R W1W1 W2W2 S US LTP: Associative n After LTP l W 1 alone  AP in R l W 2 alone  no AP in R

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

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

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

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

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

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

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

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

22. Ca 2+ -mediated Effects n Activation of protein kinases l Protein Kinase C (PKC) l Ca 2+ /calmodulin-dependent protein kinase (CaMKII) l Targets: AMPA-R & other signaling proteins n CaMKII important role l Block CaMKII  No LTP l Self-phosphorylation   LTP duration ~

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

24. Presynaptic Axon Terminal Dendritic Spine Before LTP

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

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

27. G Ca++ G NOSNO cGMP Glu G G