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

EntorhinalCortex

Dentate Gyrus

CA3

IpsilateralCA1

PerforantPathway

Mossy Fiber

SchafferCollaterals

The Entorhinal/Hippocampal System

Str

atu

m L

acu

no

som

Mo

lecu

lar

inp

uts

RecurrentConnections

Bliss and Lomo’s First Published LTP Experiment

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 System

Str

atu

m L

acu

no

som

Mo

lecu

lar

inp

uts

RecurrentConnections

SLM Inputs

Dopamine,

The Dendritic Tree

The Dendritic Spine

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 System

Str

atu

m L

acu

no

som

Mo

lecu

lar

inp

uts

RecurrentConnections

SLM Inputs

Dopamine,

StimulatingElectrode

RecordingElectrode

Electrodes in a Living Hippocampal Slice

Tissue Slice Chamber

Stimulating Schaffer Collaterals

in Area CA3

Recording in Stratum Pyramidale

in Area CA1

Recording in Stratum Radiatum

in Area CA1

Stimulus Artifact

Fiber VolleyEPSP

Recording Configuration and Typical Responses in a Hippocampal Slice Recording Experiment

-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 LTP Experiment

From Nicoll et al.

Malenka et al, Bear et al, Huganir et al.

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)

-20 0 20 40 60

75

100

125

150

175

200

LTP Triggered by Theta Burst Stimulation

Voltage Clamp

Cell Body

Pairing LTP

ASSOCIATIVE LTP

German Barrionuevo and Tom Brown

Back Propagating Action Potentials

Pairing LTP

NEURONAL INFORMATION PROCESSING

MOLECULAR MECHANISMS

NMDA

APV = AP5

Graham Collingridge

-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 Block of LTP

Gly

Glu++++

----

---

+++

SynapticGlutamate Alone

CytoplasmSynaptic Cleft

Mg++

Ca++

Glu

Ca++

++++

----

Mg++

Gly

---

+++

Glutamate plusMembrane

Depolarization

CytoplasmSynaptic Cleft

Ca++

Coincidence Detection by the NMDA Receptor

Back Propagating Action Potentials

Timing of Back-propagating Action Potentials with Synaptic Activity

EP

SP

’s

SynapticActivity

NEChange in

Local excitability1

2

Synapse

LTP?

A B

The Dendritic Tree and Regulation of Action Potential Propagation

NMDAR Independent LTP

200 Hz

Mossy FiberTEA LTP

-30 -20 -10 0 10 20 30 40 50 6050

75

100

125

150

175

200

200HzAP-5

Time (min)%

Slo

pe

pE

PS

P(S

tan

dar

diz

ed t

o B

asel

ine)

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

100

120

140

160

180

200

Seconds%

bas

elin

e fE

PS

P

PTPPPF