Longterm Potentiation

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Longterm Potentiation

• COGS 551 Human Memory
• Spring semester 2007
• METU
• Annette Hohenberger

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Longterm Potentiation Synaptic Plasticity

• Learning and Memory involves synaptic plasticity
• Synaptic plasticity is brought about by changes
  in the structure and/or in the biochemistry of
  the synapses

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Longterm potentiation LTP

• LTP is a long-lasting enhancement of synaptic
  transmission in response to brief, high-frequency
  stimulation of presynaptic neurons. (Wixted
  2004259)
• LTP has been studied intensively in the
  hippocampus (part of the limbic system)
• Intense electrical stimulation of axons which
  lead from entorhinal cortex to the dentate gyrus
  gives rise to longterm stronger synaptic
  excitatory potentials in the postsynaptic neuron.

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The hippocampusas part of the limbic system
Cerebellum
Pons
Medulla oblontata Brainstem
Medulla oblongtata Brainstem
M. Mishkin, L.G.Unterleider, and K. A. Macko
(1982) Object Vision and Spatial VisionTwo
Cortical Pathways. Trends in Neuroscience
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Hippocampus
Cornu ammonis Ammon's horn
edoc.hu-berlin.de/.../HTML/chapter4.html
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The hyppocampus and related areas
http//thalamus.wustl.edu/course/limbic.html
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Entorhinal cortex
Hippocampus
Dentate gyrus
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Before we look at the biochemistry of LTP, let's
do a short Neuroscientific rehearsal-- A
synapse-- Synaptice vesicles
http//www.learner.org/channel/courses/biology/uni
ts/neuro/images.html
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2 mechanisms of synaptic plasticity

• 1. Biochemical change
• Strengthening of individual synapses through the
  increase in postsynaptic non-NMPA (AMPA)
  receptors. With more AMPA receptors present, the
  release of glutamate by the terminal buttons
  causes a larger postsynaptic potential)
• 2. Morphological/structural change
• new synapses are formed

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1.Strenthening of individual synapsesRole of
NMDA receptors in LTP

• LTP happens when electrical impulses are fired
  successively at a high rate so that the
  postsynaptic neuron is depolarized
• LTP involves a special kind of receptor the
  NMDA receptor and a special kind of transmitter
  glutamate

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The biochemistry of LPT NMDA receptors

• NMDA N-methyl-D-aspartate. That is the name of
  the drug that specifically activates it.
• The NMDA receptor controls a calcium ion channel
  whichis normally blocked by a magnesium ion Mg2.
  
• When the postsynaptic membrane is depolarized,
  the Mg2 ion is ejected and the glutamate
  molecule can open the ion channel so that Calcium
  Ca2 ions can enter it.
• This process takes place in the dendritic spine.

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The NMDA and non NMDA receptors

• The ion channel only opens when the postsynaptic
  membrane is depolarized AND when gluatamate is
  present
• The postsynaptic membrane gets depolarized
  through another receptor, a non-NMDA receptor
  (AMPA receptor). Glutmate activates this non-NMDA
  receptor upon which it lets sodium (Na) in which
  depolarizes the postsynaptic membrane
• AMPA a-Amino-3-hydroxy-5-methyl-4-isoxazole-prop
  ione acid
• Drugs that block the NMDA receptor prevent LTP

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Role of glutamate in NMDA and nonNMDA (AMPA)
receptors
NMDA receptor-dependent AMPA receptor synaptic
delivery in LTP. At hippocampal CA3-CA1
synapses, high frequency stimuli trigger enormous
glutamate release and activate postsynaptic NMDA
receptors. Calcium influx through NMDA receptors
initiates the delivery of AMPA receptors from the
recycling endosome to the postsynaptic site.
www.ehlerslab.org/.../cellular_mechanisms/1.html
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NMDA and nonNMDA receptors
bio.phys.unm.edu/552/chap12.html
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NMDA and NonNMDA receptors
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The mechanism of LTP - NMDA

• An action potential in the axon of a presynaptic
  neuron reaches the dendrite of a postsynaptic
  cell and causes its depolarization. An action
  potential runs down the axon of the postsynaptic
  cell
• The depolarization wave also floods back into the
  synapse of the dendrites. All synapses active at
  this moment, even those that are only weakly
  activated, are primed through this flooding back
  and calcium enters the NMDA receptor cells.

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2nd mechanism of synaptic placticitygrowth of
novel synapses

• Before LTP, there is one active zone of the
  postsynaptic density in the dendritic spike of
  the postsynaptic neuron.
• The postsynaptic density is a dark band in the
  postsynaptic membrane consisting of various
  proteins and enzymes.
• After LTP, the postsynaptic neuron projects a
  spike which reaches into the terminal button of
  the pre-synaptic neuron. Its postsynaptic density
  looks perforated then.

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The postsynaptic density

• The postsynaptic membrane is characterized by a
  typical thickening, the postsynaptic density
  (PSD), carrying the neurotransmitter reception
  apparatus.

synapse-web.org/anatomy/chemical/psd.gif
synprot.ifn-magdeburg.de8100/.../mbrain.html
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Formation of new synapses - Synaptogenesis

• The perforation of the postsynaptic density is
  only the first step that leads to a division of
  the terminal end button of the pre-synaptic and
  of the dendritic spine of the postsynaptic neuron
• After LTP, the number of synapses has grown

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Formation of new synapses - Synaptogenesis
www.unige.ch/.../ToniN/these_body.html
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Short animations on LTP
http//www.learner.org/channel/courses/biology/uni
ts/neuro/images.html
Increased Receptor Sensitivity In LTP, it is now
known that the postsynaptic neuron becomes more
sensitive to neurotransmitter in a variety of
ways. One way is that phophorylation of the
glutamate receptor causes it to pass more
excitatory ions upon subsequent stimulation. View
Quicktime Movie Long-Term Potentiation In LTP,
neurons continue to fire at an elevated rate,
even though the stimulus has returned to
normal. View Quicktime Movie LTP
Mechanisms The two main hypotheses to explain
LTP are presynaptic, in which increased
neurotransmitter is released and postsynaptic,
in which sensitivity to neurotransmitter is
somehow increased. View Quicktime Movie
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Longterm depression LTD

• Learning goes both ways The opposite process of
  LTP is Longterm depression, LTD.
• LTD also works via NMDA receptors. It leads to
  the weakening of synapses and a decrease in AMPA
  receptors

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LTP vs. LTD

• LTD
• Learned input fades --gt forgetting
• A concurrent input that is not correlated with a
  strong input is weakened
• Concurrent input that is correlated with
  non-activation of the postsynaptic neuron is
  weakened, as in weak depolarization or
  hyperpolarization

• LTP
• New sensory input becomes firmly learned and
  memorized in the long term
• A concurrent input that is correlated with a
  strong input is strengthened --gt Classical
  conditioning, associative learning

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The three panels illustrate the consequences of
applying a tetanic stimulus to synaptic inputs
difering in strength. (a) A strong input alone
elicits LTP, but (b) not a weak input alone.
(c) However, when a both inputs, the strong
and the weak, occur simultaneously, this
situation gives rise to LTP in both. This
phenonenon, which is called associative LTP,
supports the contention that LTP represents a
neural mechanism underlying learning.
www.chemistry.emory.edu/justice/seminar/ltp.htm
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Other forms of LTP

• LTP has been predominantly studied in the
  hippocampus. However, it occurs in other parts of
  the brain also PFC, motor cortex, visual cortex,
  etc.
• There exists LTP without NMDA receptors, however,
  little is known about these processes.

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Range of LTP

• LTP occurs on the range of a few hours over a
  couple of days to weeks . It is, however, NOT the
  way in which memories are permanently stored
  (Wixted 2004259)

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Hightened level of activation through LTP
http//users.rcn.com/jkimball.ma.ultranet/BiologyP
ages/L/LTP.html
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References

• Carlson, Neil R. (2004) Physiology of behavior.
  Boston Pearson Education, Inc. Chapter 13
  Learning and memory. Basic Mechanisms, 410-450.
• Wixted, Joh (2004) The psychology and
  neuroscience of forgetting. Annu. Rev. Psychol.
  55, 235-269.