psy397 lecture 4
DESCRIPTION
lec 4 LTPTRANSCRIPT
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Long-term PotentiationLong-term Potentiation
Ruxandra Luca
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The Cellular and Molecular The Cellular and Molecular Basis of CognitionBasis of Cognition
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From Sidney Harris
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True or False?
How complex memories are stored and recalled at the neural circuit level, is very well understood. False
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Learning and Memory is measured by observing behaviour
Cellular changes specific changes in neurons alters the nervous system change in behaviour
Therefore learning and memory are a result of changes in behaviour and are therefore linked to changes in the cellular level
So what are the cellular changes?
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Changes at the Cellular Level Bring About Synaptic Plasticity Synaptic plasticity: alterations of synaptic
connections between neurons, which subserves learning and memory
Neuron to neuron communications are made possible by synapses
At the synapse, neurotransmitters are released in response to excitation of the presynaptic neuron, which then diffuses across the synaptic cleft, binding to receptors on the postsynaptic cell
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““Hebb’s Postulate”:Hebb’s Postulate”:
When an axon of cell A … excites cell B and When an axon of cell A … excites cell B and repeatedly or persistently takes part in firing repeatedly or persistently takes part in firing it, some growth process or metabolic change it, some growth process or metabolic change takes place in one or both cells so that A’s takes place in one or both cells so that A’s efficiency as one of the cells firing B is efficiency as one of the cells firing B is increased. increased.
D.O. Hebb, D.O. Hebb, The Organization of BehaviorThe Organization of Behavior, , 1949.1949.
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Memories are stored as alterations in the Memories are stored as alterations in the strength of synaptic connections between strength of synaptic connections between neurons in the CNS.neurons in the CNS.
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TVP Bliss, FRS
The discovery of LTPThe discovery of LTP
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In vivo recording from the rabbit hippocampusIn vivo recording from the rabbit hippocampus
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The Entorhinal/Hippocampal SystemThe Entorhinal/Hippocampal System
EntorhinalCortex
Dentate Gyrus
CA3
IpsilateralCA1
PerforantPathway
Mossy Fiber
SchafferCollaterals
Str
atu
m L
acu
no
som
Mo
lecu
lar
inp
uts
RecurrentConnections
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Bliss and Lomo’s First Published Bliss and Lomo’s First Published LTP ExperimentLTP Experiment
No tetanic stimulation
Tetanic stimulation
High frequency synaptic stimulation, resulting in LTP
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Lateral Septum,
Contralateral CA1
EntorhinalCortex
Dentate Gyrus
CA3
IpsilateralCA1
PerforantPathway
Mossy Fiber
EntorhinalCortex
Subiculum Lateral Septum
Amygdala,Cortex
SchafferCollaterals
Norepinephrine,
Acetylcholine,
Serotonin
GABAergic Interneuron
CA1 Axon
Schaffer Collaterals
The Entorhinal/Hippocampal SystemThe Entorhinal/Hippocampal System
Str
atu
m L
acu
no
som
Mo
lecu
lar
inp
uts
RecurrentConnections
SLM Inputs
Dopamine,
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The Dendritic Tree with a single axon The Dendritic Tree with a single axon passing throughpassing through
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The Dendritic Spines: thousands of contact The Dendritic Spines: thousands of contact points (synapses) points (synapses)
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View of pre- & post-synaptic View of pre- & post-synaptic terminalsterminals
DS = dendritic spineSp = Synapse (postsynaptic terminal)AT = Axon (pre-synaptic) terminalArrows indicate synaptic density
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Lateral Septum,
Contralateral CA1
EntorhinalCortex
Dentate Gyrus
CA3
IpsilateralCA1
PerforantPathway
Mossy Fiber
EntorhinalCortex
Subiculum Lateral Septum
Amygdala,Cortex
SchafferCollaterals
Norepinephrine,
Acetylcholine,
Serotonin
GABAergic Interneuron
CA1 Axon
Schaffer Collaterals
The Entorhinal/Hippocampal SystemThe Entorhinal/Hippocampal System
Str
atu
m L
acu
no
som
Mo
lecu
lar
inp
uts
RecurrentConnections
SLM Inputs
Dopamine,
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StimulatingElectrode
RecordingElectrode
Electrodes in a Living Hippocampal SliceElectrodes in a Living Hippocampal Slice
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Tissue Slice ChamberTissue Slice Chamber
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Stimulating Stimulating Schaffer CollateralsSchaffer Collaterals
in Area CA3in Area CA3
Recording inRecording in Stratum PyramidaleStratum Pyramidale
in Area CA1in Area CA1
Recording in Recording in Stratum RadiatumStratum Radiatum
in Area CA1in Area CA1
Stimulus ArtifactStimulus Artifact
Fiber VolleyFiber VolleyEPSPEPSP
Recording Configuration and Typical Responses in a Recording Configuration and Typical Responses in a Hippocampal Slice Recording ExperimentHippocampal Slice Recording Experiment
Cell body layer
Dendritic regions
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-20 0 20 40 60 80 1000
1
2
3
Time (min)
No
rmal
ized
Initi
al S
lope
-20 0 20 40 60 80 1000
1
2
3
Time (min)
No
rmal
ized
Initi
al S
lopeB
A Input/Output
0 10 20 30 400
250
500
750
Stimulus Intensity ( A)
Slo
pe
fEP
SP
( V
/ms)
Fiber Volley
0 10 20 30 400.0
0.1
0.2
0.3
0.4
Stimulus Intensity ( A)
Fib
er V
olle
y A
mp
litu
de
(V
)
Input/Output vs Fiber Volley
0.0 0.1 0.2 0.3 0.40.00
0.25
0.50
0.75
Fiber Volley Amplitude ( V)
Slo
pe
fEP
SP
( V
/ms)
An Input/Output Curve and a Typical An Input/Output Curve and a Typical LTP ExperimentLTP Experiment
Delivery of 100 Hz synaptic stimulation
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Can synapses reach a maximum synaptic strength if potentiation is very long-lasting?
What happens then? elimination of synaptic plasticity But LTP is not irreversible and every synapse
will not potentiate with time
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From Nicoll et al.
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Malenka et al, Bear et al, Huganir et al.
Low frequency stimulation induces Low frequency stimulation induces Long-Term Depression (LTD)Long-Term Depression (LTD)
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Theta Pattern in Hippocampal EEG
1-voluntary movement 2-REM sleep3-still-alert 4-slow-wave sleep
Before and after a
medial septal lesion.
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…
100-Hz 100-Hz 100-Hz 100-Hz
200
msec200
msec
200
msec
10 msec between pulses
• 5-Hz burst frequency• 10 bursts per train• 3 trains, 20-sec intertrain interval
A
B
Time(min)
fEP
SP
slo
pe
(% o
f b
asel
ine)
-20 0 20 40 60
75
100
125
150
175
200
LTP Triggered by Theta Burst Stimulation
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Voltage Clamp
Cell Body
Stimulating and recording from a Stimulating and recording from a single neuron: pairing two stimulisingle neuron: pairing two stimuli
Axon
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Pairing two stimuli : Postsynaptic depolarization Pairing two stimuli : Postsynaptic depolarization + presynaptic elctric pulse leads to LTP+ presynaptic elctric pulse leads to LTP
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What Purpose does Pairing LTP Serve? It functions as a coincidence detector When there is presynaptic and postsynaptic
activity, the neuron can trigger a unique event Associatively property arises out of this
pairing For instance, low-frequency synaptic activity
with postsynaptic depolarization can actually lead to LTP
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Gly
Glu++++
----
---
+++
SynapticGlutamate Alone
CytoplasmCytoplasmSynaptic CleftSynaptic Cleft
Mg++
Ca++
Glu
Ca++
++++
----
Mg++
Gly
---
+++
Glutamate plusMembrane
Depolarization
CytoplasmCytoplasmSynaptic CleftSynaptic Cleft
Ca++
The NMDA Receptor is a coincidence detectorThe NMDA Receptor is a coincidence detector
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Experimental set up for the analysis of the Experimental set up for the analysis of the associative nature of LTPassociative nature of LTP
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ASSOCIATIVE NATURE OF LTPASSOCIATIVE NATURE OF LTP
German Barrionuevo and Tom Brown
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Back Propagating Action Potential: From soma to dendrite
stimulation
recording
recording
Action potential K+ current
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When postsynaptic depolarization precedes When postsynaptic depolarization precedes presynaptic neurotransmitter release synaptic presynaptic neurotransmitter release synaptic
depression occurs.depression occurs.
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Pairing LTPPairing LTP
TTX = tetrodotoxinTTX = tetrodotoxin(Na+ channel blocker (Na+ channel blocker inhibiting dendritic inhibiting dendritic action potential)action potential)
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NEURONAL INFORMATION PROCESSINGNEURONAL INFORMATION PROCESSING
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MOLECULAR MECHANISMSMOLECULAR MECHANISMS
NMDANMDA
APV = AP5APV = AP5(NMDA-R antagonist)(NMDA-R antagonist)
Graham CollingridgeGraham Collingridge
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-20 0 20 40 60
75
100
125
150
175
200
225Vehicle50 M APV
APV
Time(min)
fEP
SP
slo
pe
(% o
f b
asel
ine)
APV blocks LTP inductionAPV blocks LTP induction
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EP
SP
’s
SynapticActivity
NE, Ach, S receptorsChange in
Local excitability1
2
Synapse
LTP?
A B
The Dendritic Tree and Regulation of Action The Dendritic Tree and Regulation of Action Potential PropagationPotential Propagation
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NMDAR Independent LTPNMDAR Independent LTP200 Hz200 Hz
Mossy FiberMossy FiberTetra-ethyl ammonium (K+ channel Tetra-ethyl ammonium (K+ channel blocker) induced LTPblocker) induced LTP
-30 -20 -10 0 10 20 30 40 50 6050
75
100
125
150
175
200
200HzAP-5
Time (min)
% S
lop
e p
EP
SP
(Sta
nd
ard
ized
to
Bas
elin
e)
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Question
Theoretically, would an agent that blocks potassium channels be able to induce LTP? Yes. If it increases
membrane excitability, there is an increased chance that it will
For instance TEA+ (tetraethylammonium) ion application
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-90 -60 -30 0 30 60 90 120 150 18080
100
120
140
160
180
200
Seconds%
bas
elin
e fE
PS
P
PTPPTPPPFPPF
Other forms of synaptic plasticity: pre-pulse Other forms of synaptic plasticity: pre-pulse facilitation and post-tetanic potentiationfacilitation and post-tetanic potentiation
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Synaptic strengthening: changes that may underlie LTPSynaptic strengthening: changes that may underlie LTP
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LTP= long-lasting change in output in response to transient input= learning