Transcript Slide

LONG-TERM POTENTIATION (LTP)
Introduction
LTP as a candidate mechanism for the activity-dependent
change in the strength of synaptic connections
LTP is a persistent increase in synaptic strength (as
measured by the amplitude of the EPSP) that can be
rapidly induced by brief neural activity.
Anatomical background for Hippocampus
1.
2.
3.
two interlocking C-shaped regions (the hippocampus and the dentate
gurus),
main inputs: entorhinal cortex
three major afferent pathways (subiculum -> CA1)
• Perforant pathway (subiculum -> granule cells in dentate gyrus)
• Mossy fiber pathway (axons of the granule cells -> pyramidal cells
in the CA3)
• Schaffer collaterals (pyramidal cells in the CA3 -> pyramidal cells
in the CA1)
Mossy fiber
pathway
Perforant
pathway
entorhinal
cortex
subiculum
• Perforant pathway
(subiculum -> granule
cells in dentate gyrus)
• Mossy fiber pathway
(axons of the granule
cells -> pyramidal cells
in the CA3)
• Schaffer collaterals
(pyramidal cells in the
CA3 -> pyramidal cells
in the CA1)
dentate
gyrus
CA3
Schaffer
collaterals
CA1
The initial finding by Timothy Bliss and Terje Lomo (1973)
•Anaesthetized rabbit
•Brief, high-frequency stimulation of the perforant pathway input
to the dentate gyrus produced a long lasting enhancement of the
extracellular recorded field potential.
Recording techniques
In vivo (in awake and freely moving animals, or in anesthetized
animals)
in vitro (slice preparations)
Extracellar recordings
intracellular recordings
Experimental design
Stimulation of a bundle of presynaptic axons
recording of monosynaptic EPSP
Typical results for induction of LTP
before
after
The "classical properties" of LTP
Cooperativity
The probability of inducing LTP, or the magnitude of the
resulting change, increases with the number of stimulated
afferents.
Associativity
• associativity was shown in preparations in which two
distinct axonal inputs converged onto the same
postsynaptic target
• Concurrent stimulation of weak and strong synapses to
a given neuron strengthens the weak ones.
Input specificity
LTP is restricted to only the inputs that received the
tenanic (high-frequency) stimulation
Underlying molecular mechanisms
1. Introduction
1. LTP requires some sort of additive effect
1. High-frequency stimulation
2. Activation of synapses and depolarization of the
postsynaptic neuron must occur at the same time
2. LTP (in area CA1) depends on certain changes at glutamate
synapses,
3. Types of glutamate receptors
1. NMDA receptors
2. Non-NMDA receptors, AMPA
1. At non-NMDA receptors,
1. glutamate is excitatory
2. Open channels for sodium ions
At NMDA receptors
BEFORE
1. Controls a calcium ion channel
2. glutamate is neither excitatory nor inhibitory
3. Ion channel is blocked by magnesium ions
DURING INDUCTION
1. Activation of NMDA receptors requires both glutamate and
depolarization, which lead to the removal of magnesium ions
2. The NMDA receptors now respond actively to glutamate and
admit large amount of Ca2+ through their channels
3. After induction of LTP, transmission at non-NMDA receptors is
facilitated (entry of Na+)
LTP is induced via a cascade of neurochemical steps
1. The entry of Ca2+ ions into neurons activates some protein
kinases (which are enzymes that catalyze phosphorylation, the
addition of phosphate groups to protein molecules).
2. One of the kinase, Calcium-calmodulin kinase (CaM kinase)
remains activated once it is put into that state by Ca2+, even if
the level of Ca2+ subsequently falls
3. The activated protein kinases also trigger the synthesis of
proteins
1. activate cAMP responsive element-binding protein (CREB)
2. CREB -> production of the transcription (mRNA) of
immediate early genes (IEGs) -> regulate the expression of
particular late effector genes (LEGs) -> synthesis of
proteins
4. Induction of LTP requires a retrograde signal, from the
postsynaptic neuron to the presynaptic neuron