Molecular mechanisms of memory

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Molecular mechanisms of memory
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• How does the brain achieve Hebbian plasticity?
• How is the co-activity of presynaptic and
  postsynaptic cells registered and stored?

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• Experiments in the 1980s showed that blockade of
  a particular type of glutamate receptor prevented
  the induction of LTP without interfering with
  synaptic transmission.
• When this receptor was blocked, the synapse still
  worked (release of transmitter from the
  presynaptic neuron produced a normal postsynaptic
  response)
• However, it could be cause LTP.

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• A second experiment showed that LTP could not
  occur if calcium was prevented from rising in the
  postsynaptic cell during action potentials.
• These two findings converged, because the special
  glutamate receptor controls calcium in the
  postsynaptic cell during action potentials.

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• Recall that glutamate is the main excitatory
  neurotransmitter in the brain.
• When it is released from presynaptic terminals
  and binds to postsynaptic receptors, it increases
  the likelihood that the postsynaptic neuron will
  fire.

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• There are several types of glutamate receptors.
• The AMPA receptor is involved in regular synaptic
  transmission
• The NMDA receptor is involved in synaptic
  plasticity.
• There are others, but not involved here.

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• Presynaptically released glutamate binds to both
  AMPA and NMDA receptors.
• Binding of glutamate to AMPA receptors is the
  normal way that a postsynaptic cell is induced to
  fire.

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• In contrast, when presynaptically released
  glutamate reaches NMDA receptor on the
  postsynaptic cell, it has no initially because
  part of the receptor is blocked.
• However, one glutamate has caused the
  postsynaptic cell to fire an action potential by
  binding to the AMPA receptors, the block on the
  NMDA receptor is rmoved.
• Glutamate can then open the NMDA receptor channel
  and allow calcium to enter the cell.
• LTP is the result.

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• For NMDA receptors to pass calcium, both
  presynaptic and postsynaptic cell must be active.
• This is the requirement for Hebbian plasticity.

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• Why is calcium entry through NMDA receptors a
  means of forming associations between a strong
  and a weak input?

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• Activity in the weak input pathway results in the
  release of glutamate and the binding of glutamate
  to postsynaptic receptors.
• Because the connection is weak, however, the
  input is not capable on its own of making the
  postsynaptic cell fire an action potential.
• However, when synaptic activity in the strong
  pathway activates the postsynaptic cell, the
  block on NMDA receptors will be removed, even at
  the weak synapses.

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• If the weak pathway releases glutamate at the
  same time that the strong pathway causes an
  action potential, the NMDA receptors at both the
  strong and the weak synapses will be able to bind
  the glutamate.
• Calcium will flow in through the NMDA receptors,
  and the weak synapses will be strengthened.

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• In summary, the reason that NMDA receptors allow
  LTP to occur is that they are coincidence
  detectors they are able to register that
  presynaptic and postsynaptic neurons are active
  at the same time.
• NMDA receptors allow the cell to record exactly
  which presynaptic inputs were active when the
  postsynaptic cell was firing.
• This input specificity is key to association,
  which is exactly what Hebb described.

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Long term memory

• The binding of glutamate to its receptors is a
  brief event.
• Memories can be long term.
• Biological and chemical changes must occur that
  outlast the synaptic activation by NMDA.

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• Changes in synapses have been studied use two
  procedures
• Early LTP is a form of Hebbian LTP that lasts
  only an hour or so
• Late LTP is more persistent
• Early and late LTP are commonly considered
  analogs of short-term and long-term memory.

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• Short- and long-term memory are distinguished by
  their chemical requirements, in addition to their
  longevity.
• Known for several decades that if animals are
  given drugs that prevent the brain from making
  new proteins, they are able to learn normally
  (short term) but are unable to form long-lasting
  memories.

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• If the animals are tested within an our of
  learning some task, they perform well, but when
  they are tested the next day, they show no sign
  of having learned the task.

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• This requirement for protein synthesis is true
  for most if not all kinds of memory, and for most
  if not all species.
• Blockade of protein synthesis has no effect on
  early LTP but prevents late LTP.
• These parallels between early LTP and short term
  memory on the one hand, and late LTP and
  long-term memory on the other, are consistent
  with the idea that LTP may mediate memory.

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Second messengers in memory

• Neurotransmitters like glutamate are considered
  first messengers
• They are responsible for signaling between
  neurons.
• Second messengers initiate chemical reactions
  within neurons after the neuron is stimulated by
  the first messengers.

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Calcium is a major 2nd messenger

• We saw that, when glutamate binds to its NMDA
  receptors, calcium flows into a cell (after the
  block has been removed)
• Once this occurs, calcium directs chemical
  reactions that strengthen synaptic connections.

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• The inflow of calcium activate protein kinases,
  which are enzymes that activate other proteins.
• Protein kinases phosphorylate their target
  proteins, which transforms them from inactive to
  an active state.

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• The creation of long-lasting or late LTP, like
  long term memory, requires synthesis of new
  proteins.
• This requires activation of kinases, specifically
  protein kinase A (PKA), MAP kinase (MAPK) and
  calcium/calmodulin protein kinase (CaMK)

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• These activated kinases move to the cell nucleus
  where they activate another protein, CREB.
• CREB is a transcription factor that causes the
  expression of specific genes to produce new
  proteins.
• These proteins strengthen the synapses.

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Biochemistry of LTP

• LTP in the hippocampus involves
• NMDA receptor activation
• consequent post-synaptic increase in calcium
• activation of protein kinases and other enzymes
• a partially-characterized sequence of events
  leading to increased synaptic strength

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Mutants in genes in this pathway cause changes in
learning ability
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Gene TargetingMethods exist to

• add, delete, or modify genes in the mouse genome.
• restrict expression of mouse genes to specific
  regions of the brain,
• restrict expression to specific experimental
  conditions
• high/low temperature
• presence/absence of antibiotic
• These methods can be used to create mouse models
  of human disease, e.g., Alzheimer' disease.

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• The first gene-targeting study of LTP and
  learning used mice with a null mutation for the
  alpha CaMKII gene.
• This gene responds to changes in calcium (Ca) ion
  changes related to memory formation.
• Alpha CaMKII mutants showed impaired LTP and LTD
  in the hippocampus and neocortex.

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• Although the alpha CaMKII mutant mice were
  severely impaired in the hippocampal-dependent
  version of the water maze, they were able to
  learn the "visible-platform" version of this
  task, which is known not to depend on hippocampal
  function.

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• alpha CaMKII mutants
• can learn that the platform is the only escape in
  the pool
• have the motivation to escape the water
• have the motor coordination and sensory
  perception required to efficiently swim to the
  escape platform,
• but they are unable to learn the spatial
  relationships required to guide them to the
  hidden platform.

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• CaMKII appears to be involved in the early stages
  of memory formation (during initial learning),
  but not in long-term memory formation.