Transcript LINKS BETWEEN LTP AND LEARNING AND MEMORY

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)
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 AP5induced learning deficit, although it improved
performance to some extent.
Hypo: LTP (NMDA) in Hippocampus ---- Spatial Learning
Hypo proved
Bannerman et al (Nature, 1995)
LTP
(cellular level)
Exp 1
NMDA
antagonist
Hypo: LTP (NMDA) in Hippocampus ---- Spatial Learning
Hypo disproved
Bannerman et al (Nature, 1995)
LTP
(cellular level)
Exp 2
NMDA
antagonist
Hypo: LTP (NMDA) in Hippocampus ---- Spatial Learning
Hypo disproved?
Bannerman et al (Nature, 1995)
LTP
(cellular level)
Exp 4
NMDA
antagonist
Spatial Learning evidence 1
Escape Latency
Filed circles/bars: AP5
Open circles/bars: aCSF
Without pretraining
With pretraining
Morris and colleagues (Nature, 1995)
Spatial Learning evidence 2
Probe trials
Without pretraining
With pretraining
Morris and colleagues (Nature, 1995)
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)
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
Saucier and Cain (Nature, 1995)
LTP
(cellular level)
NMDA
antagonist
Bottom line
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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
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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
•
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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)
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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)
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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.
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)
Rioult-Pedotti, et al, (1998)
Results Part I: learning induced EPSP increase
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)
Review of LTP induction
HF
stimulation
baseline
EPSP
increase
Rioult-Pedotti, et al, (1998)
Results Part II: learning reduced capacity to generate LTP
HF stimulation
Trained
Untrained baseline
UnTrained
Open symbols: untrained (right) H
Filled Symbols: trained (left) H
HF stimulation
LTP
LF stimulation
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.
Rioult-Pedotti, et al, (2000)
Results: learning reduced capacity to generate LTP
increased capacity to generate LTD
HF stimulation
Trained
Untrained baseline
UnTrained
Y-axis expressed in RELATIVE term
(% change from baseline)
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
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)