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

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

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

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.

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

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

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

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

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

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

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.

LTP (cellular level) NMDA antagonist Hypo: LTP (NMDA) in Hippocampus ---- Spatial Learning Hypo disproved Saucier and Cain (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 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

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.

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

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

Open symbols: untrained H Filled Symbols: trained H

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

HF stimulation Review of LTP induction baseline EPSP increase

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

HF stimulation LF stimulation LTP LDP

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

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

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

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

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