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LINKS BETWEEN LTP AND LEARNING AND MEMORY Does LTP = learning? Physiological -- cognitive

LINKS BETWEEN LTP AND LEARNING AND MEMORY Does LTP = learning? Physiological -- cognitive. Evidence 1. Molecular approaches relating LTP to learning 2. Electrophysiological approaches to relating LTP to learning. 1. MOLECULAR APPROACHES.

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LINKS BETWEEN LTP AND LEARNING AND MEMORY Does LTP = learning? Physiological -- cognitive

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  1. LINKS BETWEEN LTP AND LEARNING AND MEMORYDoes LTP = learning?Physiological -- cognitive • Evidence 1. Molecular approaches relating LTP to learning 2. Electrophysiological approaches to relating LTP to learning

  2. 1. MOLECULAR APPROACHES • 1.1. Is NMDAR-Dependent LTP in the Hippocampus Crucial for Spatial Learning in the Water Maze?

  3. Morris, Anderson, Lynch & Baudry (Nature, 1986) • AP5 treatment suppressed LTP in vivo • AP5 also causes a selective impairment of place learning

  4. Hypo: LTP (NMDA) in Hippocampus ---- Spatial Learning Hypo Proved LTP (cellular level) NMDA antagonist Spatial Learning Morris and colleagues (Nature, 1986)

  5. Confounding side effects of NMDAR manipulation • - NMDARs are involved in • Sensorimotor mechanisms • Fast synaptic transmission

  6. Alterations in behaviour caused by NMDAR antagonists could result from several factors • Blockage of NMDAR-dependent LTP (or LTD) • Disruption of NMDAR-mediated sensorimotor function • Impairment of fast synaptic transmission

  7. Bannerman, Good, Butcher, Ramsay, & Morris (Nature, 1995) • A two pool technique • AP5-induced learning deficit can be almost completely prevented if rats are pretrained in a different water maze before administration of the drug (spatial pretraining). • Non-spatial pretraining can not prevent AP5-induced learning deficit, although it improved performance to some extent.

  8. Hypo: LTP (NMDA) in Hippocampus ---- Spatial Learning Hypo proved Bannerman et al (Nature, 1995) Exp 1 LTP (cellular level) NMDA antagonist

  9. Hypo: LTP (NMDA) in Hippocampus ---- Spatial Learning Hypo disproved Bannerman et al (Nature, 1995) Exp 2 LTP (cellular level) NMDA antagonist

  10. Hypo: LTP (NMDA) in Hippocampus ---- Spatial Learning Hypo disproved? Bannerman et al (Nature, 1995) Exp 4 LTP (cellular level) NMDA antagonist

  11. Spatial Learning evidence 1 Escape Latency Filed circles/bars: AP5 Open circles/bars: aCSF Without pretraining With pretraining Morris and colleagues (Nature, 1995)

  12. Spatial Learning evidence 2 Probe trials Without pretraining With pretraining Morris and colleagues (Nature, 1995)

  13. LTP evidence (EPSP slope) After high frequency stimulation Control: Increased AP5: Failed to increased Filed circles: AP5 Open circles: aCSF Morris and colleagues (Nature, 1995)

  14. Saucier and Cain (Nature, 1995) • NPC17742 blocked dentate gyrus LTP • but did not prevent normal spatial learning, if non-spatial pretraining was available • These results indicate that this form of LTP is not required for normal spatial learning in the water maze.

  15. Hypo: LTP (NMDA) in Hippocampus ---- Spatial Learning Hypo disproved Saucier and Cain (Nature, 1995) LTP (cellular level) NMDA antagonist

  16. Bottom line • Water maze task is complex and requires animals to learn the general task requirement as well as the specific location of the hidden platform • Spatial pretraining can separate the two kinds of learning • Rats first made familiar with the general task requirements and subsequently trained after receiving NMDAR antagonists could learn the spatial location as quickly as controls (report from Cain's group, 1995) or showed (to some extent) improved performance (report from Morris's group, 1995) • Robust spatial learning is possible without NMDAR-dependent LTP

  17. Limitation of the approach based on NMDAR only • Other pathways (incl. mossy-fiber pathway, the lateral perforant path to CA3 and dentate) in hippocampus display LTP that are NMDAR independent • Alteration of any one of the LTP systems within the hippocampus may not be sufficient to produce a total or even a profound deficit in spatial learning

  18. Perforant pathway (subiculum -> granule cells in dentate gyrus) • Mossy fiber pathway • (axons of the granule cells -> pyramidal cells in the CA3) • Schaffer collaterals • (pyramidal cells in the CA3 -> pyramidal cells in the CA1)

  19. 1. MOLECULAR APPROACHES • 1.1. Is NMDAR-Dependent LTP in the Hippocampus Crucial for Spatial Learning in the Water Maze? • 1.2. Knockout mutants The targeting of specific genes whose products are required for LTP has been used to evaluate the role of LTP in learning.

  20. Early studies by Tonegawa group (1992) and Kandel group (1992) • Found that disrupted genes for CaMKII and kyrosine kinase impaired both hippocampal CA1 LTP and water maze acquisition. • Sakimura et al (1995), • targeted disruption of a mouse NMDAR subunit gene • Found reduction of CA1 LTP and deficiency in spatial learning

  21. limitation in these studies • The gene disruptions were performed at embryonic stem cell stage. • Thus, could alter both developmental processes and the expression of other genes. • Animals could have anatomical physiological, and behavioural abnormalities that might play a role in the acquisition of specific tasks

  22. A mutant with effects that are regionally and temporally restricted in the brain • Tonegawa and Kandel groups (Cell, 1996) • Lack NMDARs only on CA1 pyramidal cells and only beginning during the 3rd postnatal week, which avoids most of the potential developmental defects. • Exhibit no LTP, impairment in the water maze task, and place cell deficiencies

  23. 2. ELECTROPHYSIOLOGICAL APPROACHES TO RELATING LTP TO LEARNING • 2.1. Does Learning Produce LTP-like Changes? • Learning --- LTP • 2.2. Does Induction of LTP Influence Learning? • LTP -- Learning

  24. 2. ELECTROPHYSIOLOGICAL APPROACHES TO RELATING LTP TO LEARNING • 2.1. Does Learning Produce LTP-like Changes?

  25. Sharp, McMaughton and Barnes (1989) • demonstrated that exploration behaviour produced increases in synaptic responses -- field EPSP (at the site of perforant-path dentate gyrus) • The increases persisted for a short periods of time (20-40 mins) after exploration

  26. Moser, Mathiesen, Andersen (1993) • The increase in EPSP during exploration do not reflect learning-specific changes, but result from a concomitant rise in brain temperature that is caused by the associated muscular effort. • Enhanced dentate field excitary potentials followed passive and active heating and were linearly related to the brain temperature.

  27. Rioult-Pedotti, et al, (1998) Strengthening of horizontal cortical connections following skill learning Synapses efficacy EPSP increase (cellular level) motor training LTP reduced (cellular level)

  28. Rioult-Pedotti, et al, (1998) Results Part I: learning induced EPSP increase Dark lines: trained H Hatched lines: untrained H

  29. Open symbols: untrained H Filled Symbols: trained H

  30. Strengthening of horizontal cortical connections following skill learning Synapses efficacy EPSP increase (cellular level) motor training LTP reduced (cellular level) Rioult-Pedotti, et al, (1998)

  31. Review of LTP induction HF stimulation EPSP increase baseline

  32. Rioult-Pedotti, et al, (1998) Results Part II: learning reduced capacity to generate LTP HF stimulation Trained Trained baseline Untrained baseline UnTrained Open symbols: untrained (right) H Filled Symbols: trained (left) H

  33. HF stimulation LTP LF stimulation LDP

  34. Followup of 1998 paper: Rioult-Pedotti, Friedman, & Donoghue (2000). Learning-induced LTP in neocortex. Science, 290, 533-536. Commentary paper: Martin & Morris (2001). Cortical plasticity: It's all the range! Current Biology, 11, R57-R59.

  35. Rioult-Pedotti, et al, (2000) Results: learning reduced capacity to generate LTP increased capacity to generate LTD HF stimulation Trained Trained baseline Untrained baseline UnTrained Y-axis expressed in RELATIVE term (% change from baseline)

  36. Rioult-Pedotti, et al, (2000) Results: learning reduced capacity to generate LTP increased capacity to generate LTD Y-axis expressed in ABSOLUTE term Two possibilities

  37. 2. ELECTROPHYSIOLOGICAL APPROACHES TO RELATING LTP TO LEARNING • 2.1. Does Learning Produce LTP-like Changes? • Learning --- LTP • 2.2. Does Induction of LTP Influence Learning? • LTP -- Learning

  38. 2.2.Does Induction of LTP Influence Learning? • LTP induced prior to learning might impair learning by saturating LTP processes that normally participate in the learning

  39. LTP induced prior to learning • Physiological saturation of synaptic weights should disrupt new memory encoding • McNaughton et al 1986, successful but could not be replicated

  40. Moser et al (Science, 1998, v 281, page 2038) • Destroyed hippocampus unilaterally • Implanted multiple bipolar electrodes • After saturation of LTP, found impairment of water maze task

  41. Moser et al (Science, 1998, v 281, page 2038)

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