Long-term Potentiation as a
Physiological Phenomenon
From Mechanisms of Memory by
J. David Sweatt, Ph.D.
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,
Amygdala,
Cortex
Serotonin
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,
Amygdala,
Cortex
Serotonin
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
In p u t/O u tp u t
F ib e r V o lle y
500
250
0
0 .7 5
0 .3
0 .2
0 .1
0 .0
0
10
20
30
40
0
Normalized Initial Slope
S tim ulus Intensity (  A)
B
In p u t/O u tp u t v s F ib e r V o lle y
0 .4
S lope fE P SP (  V /m s)
Fiber V olley A m plitude (  V)
750
S lope fE P SP (  V /m s)
A
10
20
30
40
0 .5 0
0 .2 5
0 .0 0
0 .0
S tim ulus Intensity (  A)
0 .1
2
1
0
0
20
40
Time (min)
0 .3
Fiber V olley Am plitude (  V )
3
-20
0 .2
60
80
100
0 .4
From Nicoll et al.
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
Back Propagating Action Potentials
Timing of Back-propagating Action
Potentials with Synaptic Activity
The Dendritic Tree and Regulation of Action
Potential Propagation
A
B
NE
1
Synaptic
Activity
2
LTP?
Synapse
Change in
Local excitability
% S lo p e p E P S P
(S tan d ardiz ed to B aselin e)
200 Hz
200
175
150
125
100
75
200Hz
A P -5
50
-3 0
-2 0
-1 0
0
10
20
30
40
50
T im e (m in )
Mossy Fiber
TEA LTP
NMDAR Independent LTP
60
% baseline fE P SP
200
180
160
140
120
100
80
-9 0 -6 0 -3 0
0
30
60
S eco n d s
PPF
PTP
90 120 150 180