1. Spike timing-dependent plasticity Guoqiang Bi Department of Neurobiology University of Pittsburgh School of Medicine

2. Temporally varying patterns of input Spatially distributed patterns of storage ??? Cajal, 1894

3. When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased. — Donald O. Hebb, 1949

4. “Cells that fire together, wire together” Question: How precise do the cells need to fire together in order to wire together?

5. 1.Spike-timing-dependent synaptic plasticity How does the timing of pre- and postsynaptic activity affect synaptic modification? 2.STDP in neuronal networks How may a network change its configuration according to the temporal structure of in input stimuli? 3.Temporal integration of STDP How is a synapse modified by natural spike trains?

8. + bicuculline + CNQX & bicuculline A. Glu - Glu + CNQX + bicuculline & CNQX B. Glu - GABA S1 S2 R2 R1 * S1 S2 R2 R1 Synaptic connectivity between cultured neurons

9. Paired pre- and postsynaptic spiking – a “true Hebbian” paradigm

10. A B C LTP induced by paired spiking with positive timing

11. A B C LTD induced by paired spiking with negative timing

12. Markram et al. 1997

13. A critical window for synaptic modification induced by correlated spiking Bi & Poo 1998

14. Froemke & Dan 2002

15. Zhang et al. 1998

16. Feldman 2000

17. Nishiyama et al. 2000

18. Bell et al. 1997

19. 1.Spike-timing-dependent synaptic plasticity Paired pre- and postsynaptic spiking induces LTP and LTD, depending on the precise spike timing STDP is sensitive to neuronal cell type STDP requires NMDA receptors 2.STDP in neuronal networks How may a network change its configuration according to the temporal structure of in input stimuli? 3.Temporal integration of STDP How is a synapse modified by natural spike trains? 1.Spike-timing-dependent synaptic plasticity Paired pre- and postsynaptic spiking induces LTP and LTD, depending on the precise spike timing STDP is sensitive to neuronal cell type STDP requires NMDA receptors 2.STDP in neuronal networks How may a network change its configuration according to the temporal structure of in input stimuli? 3.Temporal integration of STDP How is a synapse modified by natural spike trains?

20. Correlated spiking at remote synapses through convergent polysynaptic pathways – a “delay-line” mechanism

21. A 1 2 3 Polysynaptic pathways in small neural networks B 1 3 2 S 150 pA EPSC 700 pA

22. 3 2 1 S 4 IPI(ms):6040 Long-term pathway remodeling induced by repetitive paired-pulse stimulation

23. IPI(ms): 1005020 3 2 1 S Sensitivity of pathway remodeling to inter- pulse interval (IPI) of input stimuli

24. IPI(ms): 150656555 3 2 1 S 4 Dependence of pathway remodeling on inter- pulse interval (IPI) of input stimuli

25. Pathway remodeling induced by paired-pulse stimuli of different IPIs

26. IPI1  IPI2 IPI1  IPI2

27. LTP and LTD at remote synapses induced by local paired pulse stimulation A1A2 B1B2

28. 1.Spike-timing-dependent synaptic plasticity Paired pre- and postsynaptic spiking induces LTP and LTD, depending on the precise spike timing STDP is sensitive to neuronal cell type STDP requires NMDA receptors 2.Remote STDP in neuronal networks STDP occurs at synaptic sites remote to network input nodes Spike timing within the network can be coordinated by delay-lines formed by polysynaptic pathways. 3.Temporal integration of STDP 1.Spike-timing-dependent synaptic plasticity Paired pre- and postsynaptic spiking induces LTP and LTD, depending on the precise spike timing STDP is sensitive to neuronal cell type STDP requires NMDA receptors 2.Remote STDP in neuronal networks STDP occurs at synaptic sites remote to network input nodes Spike timing within the network can be coordinated by delay-lines formed by polysynaptic pathways. 3.Temporal integration of STDP

29. Temporal integration of STDP – theoretical considerations “Pan-spike” interaction “Near-neighbor” interaction

30. Temporal integration of STDP – Triplet interactions

31. A B LTP induced by a special case of “triplet” spiking Bi & Poo 1998

32. Temporally asymmetric interaction between LTP- and LTD-inducing processes

33. Froemke & Dan 2002

34. 1.Spike-timing-dependent synaptic plasticity Paired pre- and postsynaptic spiking induces LTP and LTD, depending on the precise spike timing STDP is sensitive to neuronal cell type STDP requires NMDA receptors 2.Remote STDP in neuronal networks STDP occurs at synaptic sites remote to network input nodes Spike timing within the network can be coordinated by delay-lines formed by polysynaptic pathways. 3.Temporal integration of STDP In hippocampal cultures, LTP- and LTD-inducing processes integrate asymmetrically Different systems with the same spike-timing window may have different integration rules.

35. Acknowledgements UC San Diego Mu-ming Poo (Berkeley) Benedikt Berninger (Munich) University of Pittsburgh Pakming Lau Huaixing Wang Joyeeta Dutta David Nauen