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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 • 1.1. Is NMDAR-Dependent LTP in the Hippocampus Crucial for Spatial Learning in the Water Maze? Morris, Anderson, Lynch & Baudry (Nature, 1986) – AP5 treatment suppressed LTP in vivo – AP5 also causes a selective impairment of place learning Hypo: LTP (NMDA) in Hippocampus ---- Spatial Learning Hypo Proved LTP (cellular level) NMDA antagonist Spatial Learning Morris and colleagues (Nature, 1986) 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 AP5induced learning deficit, although it improved performance to some extent. Hypo: LTP (NMDA) in Hippocampus ---- Spatial Learning Hypo Disproved LTP (cellular level) NMDA antagonist spatial pretraining Morris and colleagues (Nature, 1995) Spatial Learning 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. Hypo: LTP (NMDA) in Hippocampus ---- Spatial Learning Hypo Disproved LTP (cellular level) NMDA antagonist nonspatial pretraining Saucier and Cain (Nature, 1995) Spatial Learning 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) Spatial Learning evidence AP5: Failed to increased Filed circles/bars: AP5 Open circles/bars: aCSF Escape Latency Probe trials Morris and colleagues (Nature, 1995) 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 Non-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 Confounding side effects of NMDAR manipulation • - NMDARs are involved in – Sensorimotor mechanisms – Fast synaptic transmission 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 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 • 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) 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. 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 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 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 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 2. ELECTROPHYSIOLOGICAL APPROACHES TO RELATING LTP TO LEARNING • 2.1. Does Learning Produce LTP-like Changes? 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 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. 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) Dark lines: trained H Hatched lines: untrained H Open symbols: untrained H Filled Symbols: trained H 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) Open symbols: untrained H Filled Symbols: trained H Rioult-Pedotti, et al, (1998) Learning strengthen neural connection through LTP Range and synaptic modification Rioult-Pedotti, et al (2000) 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 • 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 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 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