1. Functional dissection of the CA3-CA1 learning rule Sam Wang Princeton University http://synapse.princeton.edu/~sam/Wang-STDP.ppt

2. Optical physiology and synaptic plasticity: synaptic plasticity: Shari Gelber Daniel O’Connor Dmitry Sarkisov Shy Shoham Megan Sullivan Gayle Wittenberg Brain scaling and evolution: evolution: Mark Burish Damon Clark Kim Hatch Harrison Hao Yuan Kueh Jennifer Shultz Matt Wagers Krysta Wyatt Laboratory of Sam Wang

3. Too many learning rules! Abbott and Nelson, Nat. Neurosci.

5. CA3-CA1 synapse of hippocampus Rich history of extracellular and single-cell recording The cell biology and plasticity literature is vast One synapse per connection Has AMPA, NMDA, mGluR,…

6. Plasticity at CA3-CA1: a separable process?

7. Is timing between single spikes sufficient to describe the actual learning rule? How different are the requirements for potentiation and depression? Are these full inverses of each other? How might the learning rule map to behavior? Can cell biology help clarify these issues conceptually? Questions at the CA3-CA1 synapse

8. Nishiyama et al. 2000 Nature 408:584 80 pairings at 5 Hz Cesium pipet solution Pike et al. 1999 Journal of Physiology 518:571 40 pairings at 5 Hz Four epochs (10 pairings each) at 10-s intervals Christie et al. 1996 Learning and Memory 3:160 900 pairings at 3 Hz Epochs (30-60 pairings each) at 5-s intervals At the CA3-CA1 synapse, pairing single APs gives… …LTP. …no change. …LTD.

9. At CA3-CA1 synapses, pairing of single spikes fails to induce potentiation Single pre+post APs 100 pairings with  t=0-7 ms (pre before post) Pairing frequency 0.1-5 Hz

10. However… In Nishiyama et al. Cesium replaced Potassium in the intracellular pipette solution This will… -depolarize neuron -block A-type K channels in dendrite -broaden action potentials

11. Potassium Cesium Cs + K+K+ pairings given at 5 Hz

12. Cs + K+K+ …can bursts of APs emulate Cs + ?

13. LTP induction requires postsynaptic bursting

14. CA1 neurons fire bursts during theta oscillation

15. Pairings must be given at high frequency tt

16. Observations on the LTP learning rule Potentiation requires postsynaptic bursts Pairings are effective at 5 Hz (near theta) …does depression have these requirements?

17. LTD occurs under many timing conditions All pairings given at 5 Hz

19. RequirementThetaBursting LTP yes yes LTD no no

20. Conclusions so far Potentiation and depression have different general induction requirements. –Potentiation: active exploration (causal, bursts, 5 Hz) –Depression: many conditions During theta, the rule acts like a phase detector. At other times, the rule is depression-only.

21. Why not explore parameter space exhaustively? …because it’s exhausting!

22. Shy Shoham Uncaging in spatial patterns: High-throughput screening of neural responses Resolution: <1 micron 30,000 locations per second

23. Subthreshold and spiking behavior for “natural” stimulation ensembles

24. Now play movie at http://synapse.princeton.edu/~sam/shoham-oconnor-movie.avi

25. Local amplification in dendritic branches

29. Strategies for separating LTD and LTP

31. LTD and LTP are separable

35. LTD is fully reversible

36. LTP is not fully reversible!

37. After being induced, LTP becomes locked in

38. The starting distribution of CA3-CA1 synapses >1 Hz >10 Hz

39. The CA3-CA1 learning rule …but dissectable? Complex…

42. Large calcium signals are evoked by co-activation of parallel fibers with the climbing fiber