1. Long-term Potentiation as a Physiological Phenomenon From Mechanisms of Memory by J. David Sweatt, Ph.D.

2. The Cellular and Molecular Basis of Cognition

3. Memories are stored as alterations in the strength of synaptic connections between neurons in the CNS. “Hebb’s Postulate”: When an axon of cell A … excites cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A’s efficiency as one of the cells firing B is increased. D.O. Hebb, The Organization of Behavior, 1949.

4. From Sidney Harris

5. Memories are stored as alterations in the strength of synaptic connections between neurons in the CNS. “Hebb’s Postulate”: When an axon of cell A … excites cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A’s efficiency as one of the cells firing B is increased. D.O. Hebb, The Organization of Behavior, 1949.

6. TVP Bliss, FRS

8. The Entorhinal/Hippocampal System Entorhinal Cortex Perforant Pathway Dentate Gyrus Stratum Lacunosom Molecular inputs Mossy Fiber CA3 Schaffer Collaterals Recurrent Connections Ipsilateral CA1

9. Bliss and Lomo’s First Published LTP Experiment

10. The Entorhinal/Hippocampal System Entorhinal Cortex Perforant Pathway Dentate Gyrus Stratum Lacunosom Molecular inputs Mossy Fiber Lateral Septum, Contralateral CA1 CA1 Axon CA3 Schaffer Collaterals Recurrent Connections GABAergic Interneuron Ipsilateral CA1 Norepinephrine, Acetylcholine, Entorhinal Cortex Dopamine, Amygdala, Cortex Serotonin SLM Inputs Schaffer Collaterals Lateral Septum Subiculum

11. The Dendritic Tree

12. The Dendritic Spine

14. The Entorhinal/Hippocampal System Entorhinal Cortex Perforant Pathway Dentate Gyrus Stratum Lacunosom Molecular inputs Mossy Fiber Lateral Septum, Contralateral CA1 CA1 Axon CA3 Schaffer Collaterals Recurrent Connections GABAergic Interneuron Ipsilateral CA1 Norepinephrine, Acetylcholine, Entorhinal Cortex Dopamine, Amygdala, Cortex Serotonin SLM Inputs Schaffer Collaterals Lateral Septum Subiculum

15. Electrodes in a Living Hippocampal Slice Stimulating Electrode Recording Electrode

16. Tissue Slice Chamber

18. Recording Configuration and Typical Responses in a Hippocampal Slice Recording Experiment Recording in Stratum Pyramidale in Area CA1 Stimulating Schaffer Collaterals in Area CA3 Recording in Stratum Radiatum in Area CA1 Stimulus Artifact Fiber Volley EPSP

19. An Input/Output Curve and a Typical LTP Experiment A B

20. From Nicoll et al.

21. Malenka et al, Bear et al, Huganir et al.

22. Theta Pattern in Hippocampal EEG 1-voluntary movement 2-REM sleep 3-still-alert 4-slow-wave sleep Before and after a medial septal lesion.

23. A 100-Hz 100-Hz 100-Hz 100-Hz 200 msec … 200 msec 200 msec 10 msec between pulses • 5-Hz burst frequency • 10 bursts per train • 3 trains, 20-sec intertrain interval B 200 175 150 fEPSP slope (% of baseline) 125 100 75 -20 0 20 40 60 Time (min) LTP Triggered by Theta Burst Stimulation

24. VoltageClamp Cell Body

25. Pairing LTP

27. ASSOCIATIVE LTP German Barrionuevo and Tom Brown

28. Back Propagating Action Potentials

29. Pairing LTP

30. NEURONAL INFORMATION PROCESSING

31. NMDA APV = AP5 MOLECULAR MECHANISMS Graham Collingridge

32. APV fEPSP slope (% of baseline) Time (min) APV Block of LTP

33. Coincidence Detection by the NMDA Receptor Cytoplasm Synaptic Cleft Synaptic Cleft Cytoplasm - - - - - - + + + + + + Ca++ Gly Gly Ca++ Mg++ Ca++ Mg++ Glu + + + + - - - - + + + + - - - - Glu Glutamate plus Membrane Depolarization Synaptic Glutamate Alone

34. Back Propagating Action Potentials

35. Timing of Back-propagating Action Potentials with Synaptic Activity

36. The Dendritic Tree and Regulation of Action Potential Propagation A B NE Change in Local excitability 1 Synaptic Activity 2 EPSP’s LTP? Synapse

37. 200 Hz Mossy Fiber TEA LTP NMDAR Independent LTP

38. PPF PTP