Long-term Potentiation as a Physiological Phenomenon
Long-term Potentiation as a Physiological Phenomenon
From Mechanisms of Memory by J. David Sweatt, Ph.D.
Stratum Pyramidale
The Cellular and Molecular Basis of Cognition
Memories are stored as alterations in the strength of synaptic connections between neurons in the CNS.
“Hebb’s Postulate”: When an axon of cell A … excites cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A’s efficiency as one of the cells firing B is increased. D.O. Hebb, The Organization of Behavior, 1949.
From Sidney Harris
Memories are stored as alterations in the strength of synaptic connections between neurons in the CNS.
“Hebb’s Postulate”: When an axon of cell A … excites cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A’s efficiency as one of the cells firing B is increased. D.O. Hebb, The Organization of Behavior, 1949.
TVP Bliss, FRS
The Entorhinal/Hippocampal System Entorhinal Cortex
Dentate Gyrus Mossy Fiber
CA3 Schaffer Collaterals
Stratum Lacunosom Molecular inputs
Perforant Pathway
Recurrent Connections
Ipsilateral CA1
Bliss and Lomo’s First Published LTP Experiment
The Entorhinal/Hippocampal System Entorhinal Cortex
Dentate Gyrus Mossy Fiber Lateral Septum, Contralateral CA1
CA3 Schaffer Collaterals
Stratum Lacunosom Molecular inputs
Perforant Pathway
CA1 Axon
Recurrent Connections
GABAergic Interneuron
Ipsilateral CA1
Entorhinal Cortex
Norepinephrine, Acetylcholine, Dopamine, Serotonin
Amygdala, Cortex
SLM Inputs
Subiculum
Lateral Septum
Schaffer Collaterals
The Dendritic Tree
The Dendritic Spine
The Entorhinal/Hippocampal System Entorhinal Cortex
Dentate Gyrus Mossy Fiber Lateral Septum, Contralateral CA1
CA3 Schaffer Collaterals
Stratum Lacunosom Molecular inputs
Perforant Pathway
CA1 Axon
Recurrent Connections
GABAergic Interneuron
Ipsilateral CA1
Entorhinal Cortex
Norepinephrine, Acetylcholine, Dopamine, Serotonin
Amygdala, Cortex
SLM Inputs
Subiculum
Lateral Septum
Schaffer Collaterals
Electrodes in a Living Hippocampal Slice Stimulating Electrode
Recording Electrode
Tissue Slice Chamber
Recording Configuration and Typical Responses in a Hippocampal Slice Recording Experiment Recording in Stratum Pyramidale in Area CA1
Stimulating Schaffer Collaterals in Area CA3
Recording in Stratum Radiatum in Area CA1
Stimulus Artifact Fiber Volley EPSP
An Input/Output Curve and a Typical LTP Experiment Fiber Volley Amplitude ( V)
500
250
0
0.75
0.3
0.2
0.1
0.0 0
10
20
30
40
0
Normalized Initial Slope
Stimulus Intensity ( A)
B
Fiber Volley
0.4
Slope fEPSP (V/ms)
Input/Output
750
Slope fEPSP (V/ms)
A
10
20
30
40
Input/Output vs Fiber Volley
0.50
0.25
0.00 0.0
Stimulus Intensity ( A)
0.1
2
1
0 0
20
40 Time (min)
0.3
Fiber Volley Amplitude ( V)
3
-20
0.2
60
80
100
0.4
Malenka et al, Bear et al, Huganir et al.
Theta Pattern in Hippocampal EEG
1-voluntary movement 2-REM sleep 3-still-alert 4-slow-wave sleep Before and after a medial septal lesion.
LTP Triggered by Theta Burst Stimulation A
100-Hz
100-Hz
100-Hz
200 msec
200 msec
100-Hz
…
200 msec
10 msec between pulses
• 5-Hz burst frequency • 10 bursts per train • 3 trains, 20-sec intertrain interval
B (% of baseline)
fEPSP slope
200 175 150 125 100 75
-20
0
20
Time (min)
40
60
Voltage Clamp
Cell Body
Pairing LTP
ASSOCIATIVE LTP
German Barrionuevo and Tom Brown
Back Propagating Action Potentials
Pairing LTP
NEURONAL INFORMATION PROCESSING
MOLECULAR MECHANISMS
Graham Collingridge NMDA
APV = AP5
APV Block of LTP APV fEPSP slope (% of baseline)
225
Vehicle 50 M APV
200 175 150 125 100 75 -20
0
20 Time (min)
40
60
Coincidence Detection by the NMDA Receptor Synaptic Cleft
+ + Gly +
-
Cytoplasm
Synaptic Cleft
Gly -
Ca++
+ + +
Cytoplasm
Ca++ Mg++
Ca++
Mg++
Glu
+ + + +
-
Synaptic Glutamate Alone
Glu
-
+ + + +
Glutamate plus Membrane Depolarization
Does Long-Term Potentiation have anything to do with Memory?
NMDA Receptor Antagonist D-AP5 DL–AP5
Saline
A
L–AP5
B
40 30
Transfer test 1
Transfer test 2
Control
CSF
AP5
AP5
N=20
N=10
N=6
30 20
30
10
Control
Adj / L Train Adj / R Opp
Adj / L Train Adj / R Opp
Adj / L Train Adj / R Opp
0
R. Morris
0 40
20
10
C
10
DL-AP5
0
Adj / L Train Adj / R Opp
Quadrants time
40
Quadrants time
20
L-AP5
Saturating Hippocampal LTP Occludes Morris Water Maze Learning A
Morris, Moser (x2), et al.
B
Whitlock, Bear, et al.
Sacktor et al.
Complexities of Long-Term Potentiation
%baseline fEPSP
200 180 160 140 120 100 80 -90 -60 -30
0
30 60 90 120 150 180
Seconds
PPF
PTP
% Slope pEPSP
(Standardized to Baseline)
200 Hz
200 175 150 125 100 75 50 -30 -20 -10
200Hz AP-5 0
10
20
30
40
50
Time (min)
Mossy Fiber TEA LTP
NMDAR Independent LTP
60
Back Propagating Action Potentials
Pairing LTP
The Dendritic Tree and Regulation of Action Potential Propagation A
B
NE 1
Synaptic Activity
2
LTP? Synapse
Change in Local excitability
Modulation of LTP induction
A
Thomas, Moody, Makhinson and O’Dell (1996) Neuron 17:475-482.
B
Johnston, Hoffman, Colbert, and Magee (1999) Curr. Opin. Neurobiol. 9:288-292.
C
Gottschalk, Pozzo-Miller and Figurov (1998) J. Neurosci. 18:6830-6839
Timing of Back-propagating Action Potentials with Synaptic Activity
Potential Sites of Synaptic Modification in LTP Retrograde Signal Release Membrane Properties
Glu Binding Reuptake
Presynaptic = Altered •Neurotransmitter amount in vesicles •Number of vesicles released •Kinetics of release •Glutamate reuptake •Probability of vesicle fusion
Postsynaptic = Altered •Number of AMPA receptors •Insertion of AMPA receptors •Ion flow through AMPA channels •Membrane electrical properties
Additional possibilities include changes in number of total synaptic connections between two cells
E-S Potentiation in area CA1 A
B
Data courtesy of Erik Roberson
Immediate, Early and Late LTP 250
EPSPSlope (Percent of Baseline)
200 150 100 50 -30
0
30
60
90
120 150 180
-30
0
30
60
90
120 150 180
250 200 150
100 50
Time (minutes) Roberson, English and Sweatt (1996) Learn. Mem. 3:1-24
Induction, Maintenance and Expression of LTP
EXPRESSION BLOCKED
EPSP MAINTENANCE BLOCKED INDUCTION BLOCKED PERIOD OF DRUG TREATMENT
time tetanus
Mechanisms of Induction, Maintenance and Expression
Induction
I-LTP maintenance
Induction Induction
Expression
E-LTP maintenance
Expression
L-LTP maintenance
Expression
Injection of PKC inhibitor PKC inhibitor
Cell Body
Candidate Retrograde Signaling Molecules Physical Coupling (i.e. Integrins)
Signal
Signal
Diffusible Messengers (i.e. NO, O2-, AA)
Silent Synapse
NMDA Receptor
AMPA Receptor Vesicle
Back propagating Action Potential
Depolarization
Silent Synapses
Depotentiation and LTD A
B
C
Lee et al. (2000) Nature 405:955-959.
Model of LTP Participation in Memory Consolidation *Sensory input
A
Consolidation Signal
PP /DG /MF
Sensory input
B
Consolidation Signal
PP /DG /MF
Sensory input
C
CA3
SC
Attention/Emotion
*
CA3
*
CA3
* *
Arousal
Consolidation Signal
PP /DG /MF
SC CA1
Ach
* *
CA1 Arousal
5HT DA NE
SC
Attention/Emotion
Arousal
5HT DA NE
Attention/Emotion
EC/PC
*
5HT DA NE
CA1
EC/PC
EC/PC
* Cerebral Cortex
Behavioral Output
Recall Signal (environmental signal)
*
= Potentiated = Active
D
Sensory input
Cerebral Cortex
* Consolidation Signal
PP /DG /MF
Behavioral Output
Recall Signal (environmental signal) = Potentiated = Active
Sensory input
E
Consolidation Signal
PP /DG /MF
Attention/Emotion
Attention/Emotion
Cerebral Cortex
Figure 27
5HT DA NE
EC/PC
EC/PC
Cerebral Cortex
L-LTP
*
CA1 Arousal
5HT DA NE
EC/PC
= Potentiated = Active
SC CA1
Arousal
Behavioral Output
Consolidation Signal
PP /DG /MF
SC
5HT DA NE
Recall Signal (environmental signal)
Sensory input
F
CA3
CA1 Attention/Emotion
= Potentiated = Active
CA3
SC
Behavioral Output
Recall Signal (environmental signal)
*
CA3
Arousal
Cerebral Cortex
Cerebral Cortex
L-LTP
**
Recall Signal (environmental signal)
*
= Potentiated = Active
*
L-LTP
Behavioral Output
Modified
**
Recall Signal (environmental signal)
*
*
= Potentiated = Active
Behavioral Output
Modified
The World’s “Deadliest” Marine Animal
Box Jellyfish Sea Wasp Species - Chironex Fleckeri
Synonyms - Box Jellyfish, Fire Medusa, Indringa. Box Jellyfish projects into pedaliums, each of which may contain up to as many as fifteen tentacles each 3 metres in length
For mobility, the Box Jellyfish contracts with a jet-like motion, shooting itself along up to speeds of 4 knots. It is presumed to have “eyes” connected to a nerve ring and the creature can take evasive action or move towards its prey.
Nematocyst (400X) ~4000/animal
The World’s Deadliest Marine Animal
From Nicoll et al.
GABA-ergic interneuron model of E-S Potentiation CA1 Axon
GABAergic Neuron
GABA
Cl-
Schaffer Collaterals
+
Diminished Cl- channel function produces increased excitability
Temporal integration in LTP induction
Membrane potential (mV)
Threshold for triggering an action potential
High Frequency Stimulation
-70 Low Frequency Stimulation
Time
Theta Frequency Stimulation 5-Hz
C
A 200 msec
200 msec
200 msec
200 msec
200 msec
Theta Frequency Stimulation Time (sec)
…
3 6 9 12
200
15
175
18 21
150
24
125
27
100
30
-20
0
20
40
Time (min)
B
Dual Recording
Stratum Pyramidale
Stratum Radiatum
60
D
2 mV 5 msec
Data and figure courtesy of Joel Selcher
5 (Normalized)
75
Population Spike Amplitude: EPSP slope
(% of baseline)
fEPSP slope
• 5-Hz frequency for 30 sec • 150 total pulses
4 3 2 1 0
0
10
20
Time during TFS (sec)
30
GABA-b receptors in temporal integration with TBS
CA1 Axon
GABAergic Neuron
-
GABA
GABA-b receptor
+ Schaffer Collaterals
Negative feedback onto presynaptic GABA-b receptors causes decrease in GABA release
Dendrites with Spines mCD8
B
Distal
A
Courtesy of Liqun Lou, Stanford University
Courtesy of E. Korkotian, The Weismann Institute
LTP Outside the Hippocampus
Shafe et al. J. Neurosci. 20:8177-8187.
Alternative Mechanisms for LTP
Renger, Egles, and Liu (2001) Neuron 29:469-484.
From Mechanisms of Memory by J. David Sweatt, Ph.D.
Stratum Pyramidale
The Cellular and Molecular Basis of Cognition
Memories are stored as alterations in the strength of synaptic connections between neurons in the CNS.
“Hebb’s Postulate”: When an axon of cell A … excites cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A’s efficiency as one of the cells firing B is increased. D.O. Hebb, The Organization of Behavior, 1949.
From Sidney Harris
Memories are stored as alterations in the strength of synaptic connections between neurons in the CNS.
“Hebb’s Postulate”: When an axon of cell A … excites cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A’s efficiency as one of the cells firing B is increased. D.O. Hebb, The Organization of Behavior, 1949.
TVP Bliss, FRS
The Entorhinal/Hippocampal System Entorhinal Cortex
Dentate Gyrus Mossy Fiber
CA3 Schaffer Collaterals
Stratum Lacunosom Molecular inputs
Perforant Pathway
Recurrent Connections
Ipsilateral CA1
Bliss and Lomo’s First Published LTP Experiment
The Entorhinal/Hippocampal System Entorhinal Cortex
Dentate Gyrus Mossy Fiber Lateral Septum, Contralateral CA1
CA3 Schaffer Collaterals
Stratum Lacunosom Molecular inputs
Perforant Pathway
CA1 Axon
Recurrent Connections
GABAergic Interneuron
Ipsilateral CA1
Entorhinal Cortex
Norepinephrine, Acetylcholine, Dopamine, Serotonin
Amygdala, Cortex
SLM Inputs
Subiculum
Lateral Septum
Schaffer Collaterals
The Dendritic Tree
The Dendritic Spine
The Entorhinal/Hippocampal System Entorhinal Cortex
Dentate Gyrus Mossy Fiber Lateral Septum, Contralateral CA1
CA3 Schaffer Collaterals
Stratum Lacunosom Molecular inputs
Perforant Pathway
CA1 Axon
Recurrent Connections
GABAergic Interneuron
Ipsilateral CA1
Entorhinal Cortex
Norepinephrine, Acetylcholine, Dopamine, Serotonin
Amygdala, Cortex
SLM Inputs
Subiculum
Lateral Septum
Schaffer Collaterals
Electrodes in a Living Hippocampal Slice Stimulating Electrode
Recording Electrode
Tissue Slice Chamber
Recording Configuration and Typical Responses in a Hippocampal Slice Recording Experiment Recording in Stratum Pyramidale in Area CA1
Stimulating Schaffer Collaterals in Area CA3
Recording in Stratum Radiatum in Area CA1
Stimulus Artifact Fiber Volley EPSP
An Input/Output Curve and a Typical LTP Experiment Fiber Volley Amplitude ( V)
500
250
0
0.75
0.3
0.2
0.1
0.0 0
10
20
30
40
0
Normalized Initial Slope
Stimulus Intensity ( A)
B
Fiber Volley
0.4
Slope fEPSP (V/ms)
Input/Output
750
Slope fEPSP (V/ms)
A
10
20
30
40
Input/Output vs Fiber Volley
0.50
0.25
0.00 0.0
Stimulus Intensity ( A)
0.1
2
1
0 0
20
40 Time (min)
0.3
Fiber Volley Amplitude ( V)
3
-20
0.2
60
80
100
0.4
Malenka et al, Bear et al, Huganir et al.
Theta Pattern in Hippocampal EEG
1-voluntary movement 2-REM sleep 3-still-alert 4-slow-wave sleep Before and after a medial septal lesion.
LTP Triggered by Theta Burst Stimulation A
100-Hz
100-Hz
100-Hz
200 msec
200 msec
100-Hz
…
200 msec
10 msec between pulses
• 5-Hz burst frequency • 10 bursts per train • 3 trains, 20-sec intertrain interval
B (% of baseline)
fEPSP slope
200 175 150 125 100 75
-20
0
20
Time (min)
40
60
Voltage Clamp
Cell Body
Pairing LTP
ASSOCIATIVE LTP
German Barrionuevo and Tom Brown
Back Propagating Action Potentials
Pairing LTP
NEURONAL INFORMATION PROCESSING
MOLECULAR MECHANISMS
Graham Collingridge NMDA
APV = AP5
APV Block of LTP APV fEPSP slope (% of baseline)
225
Vehicle 50 M APV
200 175 150 125 100 75 -20
0
20 Time (min)
40
60
Coincidence Detection by the NMDA Receptor Synaptic Cleft
+ + Gly +
-
Cytoplasm
Synaptic Cleft
Gly -
Ca++
+ + +
Cytoplasm
Ca++ Mg++
Ca++
Mg++
Glu
+ + + +
-
Synaptic Glutamate Alone
Glu
-
+ + + +
Glutamate plus Membrane Depolarization
Does Long-Term Potentiation have anything to do with Memory?
NMDA Receptor Antagonist D-AP5 DL–AP5
Saline
A
L–AP5
B
40 30
Transfer test 1
Transfer test 2
Control
CSF
AP5
AP5
N=20
N=10
N=6
30 20
30
10
Control
Adj / L Train Adj / R Opp
Adj / L Train Adj / R Opp
Adj / L Train Adj / R Opp
0
R. Morris
0 40
20
10
C
10
DL-AP5
0
Adj / L Train Adj / R Opp
Quadrants time
40
Quadrants time
20
L-AP5
Saturating Hippocampal LTP Occludes Morris Water Maze Learning A
Morris, Moser (x2), et al.
B
Whitlock, Bear, et al.
Sacktor et al.
Complexities of Long-Term Potentiation
%baseline fEPSP
200 180 160 140 120 100 80 -90 -60 -30
0
30 60 90 120 150 180
Seconds
PPF
PTP
% Slope pEPSP
(Standardized to Baseline)
200 Hz
200 175 150 125 100 75 50 -30 -20 -10
200Hz AP-5 0
10
20
30
40
50
Time (min)
Mossy Fiber TEA LTP
NMDAR Independent LTP
60
Back Propagating Action Potentials
Pairing LTP
The Dendritic Tree and Regulation of Action Potential Propagation A
B
NE 1
Synaptic Activity
2
LTP? Synapse
Change in Local excitability
Modulation of LTP induction
A
Thomas, Moody, Makhinson and O’Dell (1996) Neuron 17:475-482.
B
Johnston, Hoffman, Colbert, and Magee (1999) Curr. Opin. Neurobiol. 9:288-292.
C
Gottschalk, Pozzo-Miller and Figurov (1998) J. Neurosci. 18:6830-6839
Timing of Back-propagating Action Potentials with Synaptic Activity
Potential Sites of Synaptic Modification in LTP Retrograde Signal Release Membrane Properties
Glu Binding Reuptake
Presynaptic = Altered •Neurotransmitter amount in vesicles •Number of vesicles released •Kinetics of release •Glutamate reuptake •Probability of vesicle fusion
Postsynaptic = Altered •Number of AMPA receptors •Insertion of AMPA receptors •Ion flow through AMPA channels •Membrane electrical properties
Additional possibilities include changes in number of total synaptic connections between two cells
E-S Potentiation in area CA1 A
B
Data courtesy of Erik Roberson
Immediate, Early and Late LTP 250
EPSPSlope (Percent of Baseline)
200 150 100 50 -30
0
30
60
90
120 150 180
-30
0
30
60
90
120 150 180
250 200 150
100 50
Time (minutes) Roberson, English and Sweatt (1996) Learn. Mem. 3:1-24
Induction, Maintenance and Expression of LTP
EXPRESSION BLOCKED
EPSP MAINTENANCE BLOCKED INDUCTION BLOCKED PERIOD OF DRUG TREATMENT
time tetanus
Mechanisms of Induction, Maintenance and Expression
Induction
I-LTP maintenance
Induction Induction
Expression
E-LTP maintenance
Expression
L-LTP maintenance
Expression
Injection of PKC inhibitor PKC inhibitor
Cell Body
Candidate Retrograde Signaling Molecules Physical Coupling (i.e. Integrins)
Signal
Signal
Diffusible Messengers (i.e. NO, O2-, AA)
Silent Synapse
NMDA Receptor
AMPA Receptor Vesicle
Back propagating Action Potential
Depolarization
Silent Synapses
Depotentiation and LTD A
B
C
Lee et al. (2000) Nature 405:955-959.
Model of LTP Participation in Memory Consolidation *Sensory input
A
Consolidation Signal
PP /DG /MF
Sensory input
B
Consolidation Signal
PP /DG /MF
Sensory input
C
CA3
SC
Attention/Emotion
*
CA3
*
CA3
* *
Arousal
Consolidation Signal
PP /DG /MF
SC CA1
Ach
* *
CA1 Arousal
5HT DA NE
SC
Attention/Emotion
Arousal
5HT DA NE
Attention/Emotion
EC/PC
*
5HT DA NE
CA1
EC/PC
EC/PC
* Cerebral Cortex
Behavioral Output
Recall Signal (environmental signal)
*
= Potentiated = Active
D
Sensory input
Cerebral Cortex
* Consolidation Signal
PP /DG /MF
Behavioral Output
Recall Signal (environmental signal) = Potentiated = Active
Sensory input
E
Consolidation Signal
PP /DG /MF
Attention/Emotion
Attention/Emotion
Cerebral Cortex
Figure 27
5HT DA NE
EC/PC
EC/PC
Cerebral Cortex
L-LTP
*
CA1 Arousal
5HT DA NE
EC/PC
= Potentiated = Active
SC CA1
Arousal
Behavioral Output
Consolidation Signal
PP /DG /MF
SC
5HT DA NE
Recall Signal (environmental signal)
Sensory input
F
CA3
CA1 Attention/Emotion
= Potentiated = Active
CA3
SC
Behavioral Output
Recall Signal (environmental signal)
*
CA3
Arousal
Cerebral Cortex
Cerebral Cortex
L-LTP
**
Recall Signal (environmental signal)
*
= Potentiated = Active
*
L-LTP
Behavioral Output
Modified
**
Recall Signal (environmental signal)
*
*
= Potentiated = Active
Behavioral Output
Modified
The World’s “Deadliest” Marine Animal
Box Jellyfish Sea Wasp Species - Chironex Fleckeri
Synonyms - Box Jellyfish, Fire Medusa, Indringa. Box Jellyfish projects into pedaliums, each of which may contain up to as many as fifteen tentacles each 3 metres in length
For mobility, the Box Jellyfish contracts with a jet-like motion, shooting itself along up to speeds of 4 knots. It is presumed to have “eyes” connected to a nerve ring and the creature can take evasive action or move towards its prey.
Nematocyst (400X) ~4000/animal
The World’s Deadliest Marine Animal
From Nicoll et al.
GABA-ergic interneuron model of E-S Potentiation CA1 Axon
GABAergic Neuron
GABA
Cl-
Schaffer Collaterals
+
Diminished Cl- channel function produces increased excitability
Temporal integration in LTP induction
Membrane potential (mV)
Threshold for triggering an action potential
High Frequency Stimulation
-70 Low Frequency Stimulation
Time
Theta Frequency Stimulation 5-Hz
C
A 200 msec
200 msec
200 msec
200 msec
200 msec
Theta Frequency Stimulation Time (sec)
…
3 6 9 12
200
15
175
18 21
150
24
125
27
100
30
-20
0
20
40
Time (min)
B
Dual Recording
Stratum Pyramidale
Stratum Radiatum
60
D
2 mV 5 msec
Data and figure courtesy of Joel Selcher
5 (Normalized)
75
Population Spike Amplitude: EPSP slope
(% of baseline)
fEPSP slope
• 5-Hz frequency for 30 sec • 150 total pulses
4 3 2 1 0
0
10
20
Time during TFS (sec)
30
GABA-b receptors in temporal integration with TBS
CA1 Axon
GABAergic Neuron
-
GABA
GABA-b receptor
+ Schaffer Collaterals
Negative feedback onto presynaptic GABA-b receptors causes decrease in GABA release
Dendrites with Spines mCD8
B
Distal
A
Courtesy of Liqun Lou, Stanford University
Courtesy of E. Korkotian, The Weismann Institute
LTP Outside the Hippocampus
Shafe et al. J. Neurosci. 20:8177-8187.
Alternative Mechanisms for LTP
Renger, Egles, and Liu (2001) Neuron 29:469-484.
