Mechanisms for memory:
Introduction to LTP
Bailey Lorv
Psych 3FA3
November 15, 2010
Lecture Outline
• Synaptic Plasticity
• Long-term Potentiation
– Cellular level
– Molecular level
– As a mechanism for memory
• Long-term Depression
• Behavioural Correlates and Closing Remarks
Synaptic Plasticity
Learning as a change in synaptic strength
Short Term Synaptic Plasticity
• Facilitation
– Ca2+ abundance
• Synaptic Depression
– Neurotransmitter depletion
• Post-tetanic potentiation
Hebb’s Postulate
When an axon of cell A is near enough to
excite cell B or repeatedly or persistently takes
part in firing it, some growth process or
metabolic change takes place in one or both
cells such that A's efficiency, as one of the cells
firing B, is increased.
• Cells that fire together, wire together
Long-Term Potentiation
• Long-term facilitation of synaptic activity
• Characterized by Bliss and Lomo (1973)
• A persistent (several hours +) increase in
strength and ease of post-synaptic activation
induced by frequent high intensity electrical
activity (tetanus) in the pre-synaptic neuron
The Hippocampus
• Involved in spatial memory, formation of
declarative memory
• CA1 damage has led to memory deficits in
humans (Zola Morgan et al., 1986)
• Relatively easy to isolate intrinsic connections
Rat Hippocampal Anatomy
Perforant Pathway
Entorhinal cortex to granule cells of dendate gyrus
Mossy Fiber Pathway
Granule cells of dendate gyrus to pyramidal cells of CA3
Schaffer Collateral Pathway
Pyramidal cells of CA3 to pyramidal cells of CA1
Recording Setup
Bliss and Lomo (1973)
Results
Baseline
activation
Inducing LTP
1) Tetanus (Nicoll, Malenka and Kauer, 1988)
Fig 23.3 from Neuroscience, edited by Purves
2) Pairing pre-synaptic and post-synaptic
(Gustafsson et al., 1987)
• Single shock, not strong enough to induce LTP
• Pair (within 100 ms) with depolarizing current in
cell body
From Ch 23: Neuroscience, edited by Purves
Fig 23.4 from
Neuroscience, edited by
Purves
Molecular Mechanisms of Change
• In area C1, LTP occurs in glutamate releasing
synapses
– Glutamate antagonists (AP5) block LTP
• 2 types of glutamate receptors
– NMDA-R: Ca2+ channel
• Channel blocked by Mg2+
– Non-NMDA-R (AMPA-R): Na+ channel
• In order to free the NMDA-channel
 pre-synaptic: glutamate release
 post-synaptic: Mg2+ release, via depolarization
• Coincident detector
Fig 3.3 from Cognitive Neuroscience of Memory, by
Eichenbaum
A. Prior to depolarization
B. After depolarization
• Ca2+ -> activation of protein kinase or activation
of calmodulin-dependent protein kinase
1) Increase sensitivity of post-synaptic neuron
1. Activate cAMP responsive element-binding protein
(CREB)
2. CREB leads to transcription (mRNA) of immediate
early genes (IEGs) which regulate the expression of
particular late effector genes (LEGs)
3. Synthesis of proteins such as AMPA-R
4. Insert receptors into cell membrane
From Ch 3: Cognitive Neuroscience of Memory, by Eichenbaum
2) Using retrograde factors (i.e. NO, arachidonic
acid) -> enhances pre-synaptic release
– Unknown mechanism
• Both result in increased excitation of postsynaptic following stimulation of pre-synaptic
From Ch 3: Cognitive Neuroscience of Memory, by Eichenbaum
Why LTP may be a mechanism for
memory
1) Important component of hippocampus
2) Develops very quickly -> Can occur as quickly
as 1 min after a stimulus train
3) Persistent -> Is long lasting even in in vivo
preparations
From Ch 3: Cognitive Neuroscience of Memory, by Eichenbaum
4) Specificity
• Strengthening of only the synapse which
shows coincidental activity
Depolarization of post-synaptic
Glutamate release
5) Associativity
• Pairing of a strong and weak stimulus
• Why?
Fig 3.2 from Cognitive Neuroscience of Memory, by Eichenbaum
Long-term Depression
• Maximal efficacy problem
• Epilepsy
• Stimulate Schaffer collateral pathways at a low
rate (1 Hz) for a long period of time (10-15
minutes)
– Can reverse LTP
– Decrease activation following stimulation
• Same mechanisms as LTP – NMDA-R
– High versus low rate of increase in Ca2+
• High rate of increase in Ca2+ ->
– Activation of calcium dependent protein kinase,
CaMKII -> phosphorylation of target proteins
From Ch 23: Neuroscience, edited by Purves
Ca2+
• Low rate of increase in Ca2+ ->
– leads to activation of phosphotases -> removes
phosphate groups from target proteins
• Phosphatase blockers inhibits formation of
LTD
From Ch 23: Neuroscience, edited by Purves
Removal of NMDA-R
From Lau and Zukin, 2007
Closing remarks on LTP
• Artificial phenomenon...
• Ubiquitous Process
• Potential mechanism for memory?
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Enriched versus impoverished environments
Effects of training (Module 8)
Chemical inhibitors affects learning (Module 7)
Saturation can block learning