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

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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

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1. MOLECULAR APPROACHES

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

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Morris, Anderson, Lynch Baudry (Nature, 1986)

• AP5 treatment suppressed LTP in vivo
• AP5 also causes a selective impairment of place
  learning

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

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Hypo LTP (NMDA) in Hippocampus ---- Spatial
Learning
Hypo Disproved
LTP (cellular level)
NMDA antagonist
Spatial Learning
spatial pretraining
Morris and colleagues (Nature, 1995)
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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.

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Hypo LTP (NMDA) in Hippocampus ---- Spatial
Learning
Hypo Disproved
LTP (cellular level)
NMDA antagonist
Spatial Learning
nonspatial pretraining
Saucier and Cain (Nature, 1995)
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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)
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Spatial Learning evidence AP5 Failed to
increased
Filed circles/bars AP5 Open circles/bars aCSF
Escape Latency
Probe trials
Morris and colleagues (Nature, 1995)
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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

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Confounding side effects of NMDAR manipulation

• - NMDARs are involved in
• Sensorimotor mechanisms
• Fast synaptic transmission

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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

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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

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

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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.
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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
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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

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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

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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

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2. ELECTROPHYSIOLOGICAL APPROACHES TO RELATING
LTP TO LEARNING

• 2.1. Does Learning Produce LTP-like Changes?

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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

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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.

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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)
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Dark lines trained H Hatched lines untrained H
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Open symbols untrained H Filled Symbols trained
H
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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)
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Open symbols untrained H Filled Symbols trained
H
Rioult-Pedotti, et al, (1998)
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Learning strengthen neural connection through LTP

• Range and synaptic modification
• Rioult-Pedotti, et al (2000)

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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

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• 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

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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

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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

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