Long-term PotentiationLong-term Potentiation

Ruxandra Luca

The Cellular and Molecular The Cellular and Molecular Basis of CognitionBasis of Cognition

From Sidney Harris

True or False?

How complex memories are stored and recalled at the neural circuit level, is very well understood. False

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?

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

““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.

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.

TVP Bliss, FRS

The discovery of LTPThe discovery of LTP

In vivo recording from the rabbit hippocampusIn vivo recording from the rabbit hippocampus

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

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

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,

The Dendritic Tree with a single axon The Dendritic Tree with a single axon passing throughpassing through

The Dendritic Spines: thousands of contact The Dendritic Spines: thousands of contact points (synapses) points (synapses)

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

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,

StimulatingElectrode

RecordingElectrode

Electrodes in a Living Hippocampal SliceElectrodes in a Living Hippocampal Slice

Tissue Slice ChamberTissue Slice Chamber

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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1

2

3

Time (min)

No

rmal

ized

Initi

al S

lope

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Time (min)

No

rmal

ized

Initi

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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

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(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

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

From Nicoll et al.

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)

Theta Pattern in Hippocampal EEG

1-voluntary movement 2-REM sleep3-still-alert 4-slow-wave sleep

Before and after a

medial septal lesion.

…

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)

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75

100

125

150

175

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LTP Triggered by Theta Burst Stimulation

Voltage Clamp

Cell Body

Stimulating and recording from a Stimulating and recording from a single neuron: pairing two stimulisingle neuron: pairing two stimuli

Axon

Pairing two stimuli : Postsynaptic depolarization Pairing two stimuli : Postsynaptic depolarization + presynaptic elctric pulse leads to LTP+ presynaptic elctric pulse leads to LTP

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

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

Experimental set up for the analysis of the Experimental set up for the analysis of the associative nature of LTPassociative nature of LTP

ASSOCIATIVE NATURE OF LTPASSOCIATIVE NATURE OF LTP

German Barrionuevo and Tom Brown

Back Propagating Action Potential: From soma to dendrite

stimulation

recording

recording

Action potential K+ current

When postsynaptic depolarization precedes When postsynaptic depolarization precedes presynaptic neurotransmitter release synaptic presynaptic neurotransmitter release synaptic

depression occurs.depression occurs.

Pairing LTPPairing LTP

TTX = tetrodotoxinTTX = tetrodotoxin(Na+ channel blocker (Na+ channel blocker inhibiting dendritic inhibiting dendritic action potential)action potential)

NEURONAL INFORMATION PROCESSINGNEURONAL INFORMATION PROCESSING

MOLECULAR MECHANISMSMOLECULAR MECHANISMS

NMDANMDA

APV = AP5APV = AP5(NMDA-R antagonist)(NMDA-R antagonist)

Graham CollingridgeGraham Collingridge

-20 0 20 40 60

75

100

125

150

175

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225Vehicle50 M APV

APV

Time(min)

fEP

SP

slo

pe

(% o

f b

asel

ine)

APV blocks LTP inductionAPV blocks LTP induction

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

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

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200HzAP-5

Time (min)

% S

lop

e p

EP

SP

(Sta

nd

ard

ized

to

Bas

elin

e)

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

-90 -60 -30 0 30 60 90 120 150 18080

100

120

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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

Synaptic strengthening: changes that may underlie LTPSynaptic strengthening: changes that may underlie LTP

LTP= long-lasting change in output in response to transient input= learning