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A Persistent Postsynaptic Modification Mediates Long-Term Potentiation in the Hippocampus
J. Kauer, R. Malenka, and R. NicollNeuron vol 1, p 911-917 December 1988
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BackgroundBackground
Long Term Potentiation (LTP) - a long-lasting enhancement of synaptic transmission that can be induced by brief and repetitive stimulation of excitatory pathways in the hippocampus.
Why is LTP important?
LTP has been intensively studied as a model for information storage in the vertebrate brain and shares properties with associative learning.
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Background (cont.)
1.NMDA Receptors: – Long lasting– Sensitive to APV antagonist
2.Non-NMDA Receptors:– Shorter time course– Sensitive to CNQX antagonist
Glutamate released by the CA3 region of the hippocampus activates 2 subtypes of receptors:
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The Big Question
Where does the process causing increased synaptic transmission associated with LTP take place…Pre- or post-synaptically?
At the time of this experiment, there were 3 suggested possibilities:
1. Increased neurotransmitter release from presynaptic terminals
2. A morphological change in pre- or post-synaptic structure
3. A post-synaptic change in sensitivity to neurotransmitters
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Methods
• In this series of experiments, the LTP is induced at the Schaffer collateral-commissural synapse between the CA3 and CA1 pyramidal cells.
• Study is done on the sliced hippocampus of a rat.
• Two methods used to induce LTP– Tetanic Stimulation
– Pairing Protocol
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Tetanus vs. Pairing Protocol• A tetanus is a brief, high-frequency stimulation of pre-
synaptic neuron, which, in addition to inducing LTP, causes a 1-2 min. “Post-tetanic potentiation” (PTP) resulting from increased glutamate release from pre-synaptic terminals.
• Pairing protocol refers to a low-frequency (0.1 Hz) stimulation of the pre-synaptic neuron along with artificial intracellular depolarization of the post-synaptic neuron. This provides just enough to induce LTP, but without such strong stimulation and neurotransmitter release associated with tetanic stimulation.
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Pairing & Tetanus LTP induction by pairing EPSPs with Depolarization or by Tetanic Stimulationof the afferent pathway.
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The Premise• After LTP induction, an increase in
neurotransmitter release by the pre-synaptic neuron would result in a simultaneous increase in both EPSP components.
• It is already known that the non-NMDA mediated current increases after LTP, but to prove that more glutamate is released, it would have to be shown that the NMDA mediated current increases after LTP as well.
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Experiment 1
PROCEDURE:• LTP induced using either
– Tetanic stimulation – Pairing protocol
• Chemical antagonist CNQX was applied to block the non-NMDA receptors.
• The NMDA component of the EPSP was examined in isolation from the non-NMDA component before and after LTP using CNQX.
• Cells were monitored for 40 min. following LTP inducing stimuli.
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Experiment 1
RESULTS:
After addition of CNQX:Pairing protocol produced no lasting changes in the NMDA component of the EPSP. Tetanic stimulation induced PTP
Caused a transient increase in NMDA component, but quickly returned to baseline
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Experiment 1
INTERPRETATION:
• The NMDA component of the EPSP is not enhanced following LTP inducing stimuli.
• Since NMDA mediated response did not change after pairing and tetanus, an increase in glutamate release probably does not explain the changes in LTP.
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Experiment 2
BACKGROUND AND PROCEDURE:- Previous work has shown that activation of NMDA receptors is
required to induce LTP. - It is possible that non-NMDA are also required to induce LTP,
and that CNQX simply prevents the induction of LTP. 1. In the presence of CNQX: record EPSP from 2 independent
stimulating inputs using 2 extracellular microelectrodes:– One pathway was tetanized– The other received low frequency stimulation
2. To rule out excess neurotransmitter release from tetanus-induced PTP, recordings were repeated using the pairing protocol.
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Experiment 2
RESULTS:As CNQX washed away – 30-60 minutes
The tetanized pathway exhibited LTPThe pathway which received low
frequency stimulation returned to baseline.
As CNQX washed away, the post-synaptic cell exhibited LTP.
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Experiment 2BPROCEDURE :Intracellular and Extracellular
recording electrodes recorded EPSPs before and after the pairing protocol in the presence of CNQX.
OBSERVATIONS:-Intracellular EPSP became potentiated, while the extracellular EPSP was unaffected.
-CNQX does not interfere with the induction of LTP.
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Experiment 2 & 2B
INTERPRETATION:
This experiment demonstrates the following:
1. CNQX does not interfere with the induction of LTP.
2. LTP can be induced, even when the activity of non-NMDA receptors has been abolished.
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Experiment 3
Goal:- Show that LTP results from a selective increase in the non-NMDA component
of the EPSP.
Procedure:• Reversed EPSPs were recorded • Isolate early and late components of the EPSP by using chemical antagonist
APV that blocks the NMDA receptors. • Compare EPSPs before and after the induction of LTP, and in the presence
and absence of APV.
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Experiment 3
RESULTS:• Large increase in the amplitude of the non-NMDA (early component), after a
tetanus or pairing.
• Shows that the NMDA component (late component) is not altered after tetanus or pairing.
INTERPRETATION:• The early non-NMDA component is selectively increased following LTP
inducing stimuli.
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Summary
• Late component of EPSP enhanced only during post tetanic potentiation (PTP)
• After pairing and tetanus only the early component of the EPSP was increased.
• After a few minutes after tetanization the late component of the EPSP returned back to control level.
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Conclusions
• Results from these experiments are best explained by a modification of the postsynaptic neuron such that the non-NMDA component of the EPSP is selectively increased.
• LTP is not a result of an increase in glutamate release between the CA3 and CA1 regions.
What does this mean??
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Further thoughts• It is possible that at single post-synaptic dendritic spines,
pre-synaptic fiber stimulation, plus activation of NMDA receptors modifies neighboring non-NMDA receptors.
• The calcium dependent biochemical events are localized to the postsynaptic cell, and may either increase the number or modify the gating properties of the non-NMDA class of glutamate receptor/ion channels.
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Critiques• During Experiment 2: Adding APV and CNQX
simultaneously would make it possible to conclude that induction of LTP was from NMDA activation.
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Credits Made Possible By:
Andy ChiuStephanie ChowAaron Cheung
Kimberlyn DangCassie ColemanAlice Hue ChenRomerson Dimla
Zackary CraddockJeff DiamondGiang DinhIsaac Cho
Deepak DhaliwalMichael DouzjianMichael Dearinger
Susan ChengKrijin DijkstraSynthia Dabiri
Produced byBIPN 148 Group 2™
Animation byKim Dang, Inc. ™
Research byJ. Kauer, R. Malenka, and R. Nicoll™
2007, Group 2 Productions ™