1. Synaptic plasticity: Introduction Different induction protocols Basic properties Key elements of the biophysics Site of change: pre or post-synaptic More on Mechanism

2. Rate based induction (show on board)

4. But: Heterosynaptic LTD – from Abraham (note – in vivo) Note about the different meanings of hetero Christie et. Al 1995

5. Pairing induced plasticity Feldman, 2000 Show voltage clamp

6. Spike timing dependent plasticity Markram et. al. 1997 Anatomy figure from Markram 97

7. Spike timing dependent plasticity Markram et. al. 1997

8. Bi and Poo J. Neurosci. 1998

9. Some properties (observations) of synaptic plasticity Synapse specificity (but) Associatively (pre and post occur together) Cooperativety (two different input pathways can boost each other)

10. 1. Voltage dependence 2. Calcium permeability

11. Some key elements of the biophysics of induction 1. NMDA receptors are necessary (in many systems) for the induction of LTP and LTD Bi and Poo, 1998 Control With APV Same hold for LTD – but some forms of plasticity are NMDAR independent

12. Partial blockade of NMDA-R Cummings et. al, 1996

13. 2. Calcium influx is necessary for plasticity and its level determines the sign and magnitude of plasticity

14. And might be sufficient Yang, Tang Zucker, 1999

15. Moderate, but prolonged calcium elevation = LTD High calcium elevation = LTP ( brief is sufficient, but what will long do? ) Yang, Tang Zucker, 1999

16. High/Correlated activity HighCalcium LTP Low/uncorrelated activity Moderate Calcium Calcium LTD LTD Magic High NMDA-R activation Modelrate NMDA-R activation

17. What changes during synaptic plasticity? What is the mechanism responsible for the induction of synaptic plasticity? (magic?) Can every form of plasticity be accounted for by STDP? What are the rules governing synaptic plasticity? How is synaptic plasticity maintained?

18. Presynaptic release probability The number of postsynaptic receptors. Properties of postsynaptic receptors What can change during synaptic plasticity?

19. Possible evidence for a presynaptic mechanism 1. Change in failure rate (minimal stimulation) 2. Change in paired pulse ratio (explain on board – for both ppf and ppd) 3. The MK 801 test

20. Evidence for postsynaptic change: 1.No change in failures 2.No change in PPR 3.No change in NMDA-R component 4.Different change for AMPA and NMDA-R currents 5.No change in MK-801 Are there other possible reasons for change in PPR?

21. The story of silent synapses Concepts Minimal stimulation Effect of depolarization on NMDA-R

23. Model of synaptic plasticity

24. Summary – up to here.

25. Phosphorylation state of Gultamate receptors is correlated with LTP and LTD GluR1-4, functional units are heteromers, probably composed of 4 subunits, probably composes of different subtypes. Many are composed of GluR1 and GluR2 R1 R2 R1 P P

26. Protein Phosphorylation Non-phosphorylatedPhosphorylated Phosphorylation at s831 and s845 both increase conductance but in different ways

27. LTD- dephosphorylation at ser 845 Lee et al. 2000

28. LTP- phosphorylation at ser 831

29. Trafficking of Glutamate receptors constitutive and activity dependent. Activity dependent insertion and removal and its dependence on Phosphorylation

30. High/Correlated activity HighCalcium LTP Phosphorylation Increased conductance Increased AMPAR number Low/uncorrelated activity Moderate Calcium Calcium LTD Dephosphorylation decreasedconductancedecreased AMPAR number Magic

31. The next two topics will be: From activity to calcium “Magic” – from calcium to phosphorylation: the signal transduction pathways Keep in mind, as complex as it might seem to you, it is actually much more complex. This is a cartoon version, passed through my subjective filters (the end)

32. Here a picture of a spine, with sources and sinks of calcium Sources NMDAR VGCC Release from internal stores Sinks Diffusion Buffers Pumps

33. Calcium through NMDAR

34. For calcium channels the more precise formulation is to use the GHK equation (See Johnston and Wu pg: ) However, for simplicity we will use the simple ‘Ohmic’ formulation: j Ca

35. Ligand binding kinetics – sum of two exponentials with different time constants (Carmignoto and Vicini, 1992) Calcium Dynamics- first order ODE 0.7 0.5 0.0 NMDA receptor kinetics- sum of two exponents ms Ca 25 

36. Show calcium transients at low and high postsynatic voltage. Talks about NMDA-R as a coincidence detector

37. Magic A brief summary of the signal transduction pathway leading from Calcium to Phosphorylation/ Dephosphorylation =