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 LatencyFiled circles/bars: AP5Open circles/bars: aCSF

Morris and colleagues (Nature, 1995)

Without pretraining

With pretraining

Probe trialsSpatial Learning evidence 2

Without pretraining

With pretraining

Morris and colleagues (Nature, 1995)

LTP evidence (EPSP slope)After high frequency stimulationControl: IncreasedAP5: Failed to increased

Morris and colleagues (Nature, 1995)

Filed circles: AP5Open 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 geneFound 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 efficacyEPSP increase(cellular level)

motor training

Rioult-PedottiRioult-Pedotti, et al, (1998)

Strengthening of horizontal cortical connections following skill learning

Dark lines: trained HHatched lines: untrained H

Rioult-PedottiRioult-Pedotti, et al, (1998)Results Part I: learning induced EPSP increase

Open symbols: untrained HFilled Symbols: trained H

LTP reduced(cellular level)

Rioult-PedottiRioult-Pedotti, et al, (1998)

Synapses efficacyEPSP 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-PedottiRioult-Pedotti, et al, (1998)Results Part II: learning reduced capacity to generate LTP

Untrained baselineUntrained baseline

Open symbols: untrained (right) HFilled 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, 533-536.

Commentary paper:Martin & Morris (2001). Cortical plasticity: It's all the range! Current Biology, 11, R57-R59.

HF stimulation

Trained

UnTrainedUntrained baselineUntrained baseline

Rioult-PedottiRioult-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-PedottiRioult-Pedotti, et al, (2000)Results: learning reduced capacity to generate LTP increased capacity to generate LTD

Two possibilitiesY-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)