BIPN 140: Cellular Neurobiology

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BIPN 140 Cellular Neurobiology LECTURE 15
Learning Memory
Website http//www.biology.ucsd.edu/classes/bip
n140.FA07
INSTRUCTORS Nicholas C. Spitzer
(nspitzer_at_ucsd.edu) Darwin K. Berg
(dberg_at_ucsd.edu)
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Summary Nicotinic Signaling Helps Guide
Development in Multiple Ways
Endogenous nicotinic activity determines when
GABA signaling converts from excitation to
inhibition during development.
Nicotinic activity also collaborates with
GABAergic inhibition to regulate innervation.
Nicotinic activity through ?2-nAChRs induces
spines (without Glu/GABA help). Nicotinic
stimulation of ?7-nAChRs enables presynaptic
boutons to innervate the spines and recruits AMPA
receptors to the spine surface. Together, ?2-
and ?7-nAChRs can help promote glutamatergic
synapse formation.
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Fig 23.7a Molecular Mechanisms Involved in
Synapse Formation
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Fig 23.7b Molecular Mechanisms Involved in
Synapse Formation
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Fig 23.7c Molecular Mechanisms Involved in
Synapse Formation
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Fig 23.8a,b Potential Molecular Mediators of
Synapse Identity
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Fig 23.8c Potential Molecular Mediators of
Synapse Identity
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Figure 31.1 The major qualitative categories of
human memory
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Figure 31.2 The major temporal categories of
human memory
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Figure 31.7a Areas that, when damaged, tend to
give rise to declarative memory disorders
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Figure 31.7b Areas that, when damaged, tend to
give rise to declarative memory disorders
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Figure 31.7c Areas that, when damaged, tend to
give rise to declarative memory disorders
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Memory for places learned long ago is intact
after hippocampal damage. by Edmond Teng
Larry R. Squire
Nature 400 675-677 (1999)
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BACKGROUND The hippocampus is assumed to be
the site of declarative memory formation.
(Remember the movie Memento?) For years it was
thought to be particularly dedicated to spatial
memories, though now we know it to be critical
for essentially all declarative memory
formation. Questions Is the hippocampus the
site of memory storage? Is the hippocampus
needed for memory recall?
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EXPERIMENTS Larry Squire and his group
identified a patient who had become severely
amnesic at 69 because of a viral infection that
destroyed his hippocampus. (The patient had
moved to Encinitas afterward during these tests,
he never recognized his examiners despite 40
visits.) In his youth, the patient grew up in
Hayward. To test his recall of spatial memories
encoded prior to the hippocampal damage, Larrys
group asked him questions about Hayward streets
in those early days. Questions How would you
assess his accuracy? How would you determine if
his performance was normal?
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Map of Haward-Castro Valley in the 1940s

• Points of reference for recall
• Bret Harte School
• Hayward Union High School
• Hayward Theatre
• Castro Valley Grammar School

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Performance on Spatial Recall
A) Percentage of proposed routes that were
correct. B) Frequency of error Patient filled
circles Control peer group open circles.
BUT, when tested for knowing routes at current
address, peers were correct 100 of time patient
was correct 0 of time, confirming his inability
to form and/or recall new spatial memories.
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TAKEHOME RESULT The hippocampus is necessary for
the formation of declarative memories but it is
not the permanent site of storage for those
memories nor is it required for retrieval of
those memories.
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Postsynaptic Receptor Trafficking Underlying a
Form of Associative Learning by S Rumpel, J
LeDoux, A. Zador, and R. Malinow
Science 30883-88 (2005)
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BACKGROUND LTP was long thought to represent
a cellular basis for learning and memory because
(1) it represent a long-lasting change in circuit
function, (2) drugs (APV) that blocked NMDA
receptors blocked both LTP and common forms of
memory, and (3) NMDA receptor knockouts impaired
both memory formation and LTP. But these results
did not provide hard proof that LTP was necessary
for learning and memory. Drugs are notoriously
pleiotropic and there could be multiple parallel
effects of the KOs and drug treatments (hence
correlative instead of causal).
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EXPERIMENTS Record from the amydala, a brain
region known to play a key role in formation of
fear-related memories. Test the ability of the
animals to associate a tone with a shock
(auditory fear conditioning). Use a viral
construct to express mutant GluR1-containing AMPA
receptors locally in the amygdala of living mice.
Determine whether wildtype constructs express
locally and function normally but do not perturb
the system (control). Then test mutant
construct that prevents AMPA receptor insertion
into the surface and see if it (1) blocks LTP and
(2) blocks auditory fear conditioning.
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Fig. 3 Associative learning drives
GluR1-containing AMPA receptors into synapses on
the postsynpatic cell
A Training recording protocol for paired
(expt) and unpaired (control) virally injected
animals followed by recording of evoked AMPA
PSCs. Note the virally injected receptor
construct rectifies when tested. C In the
paired (trained) animals, the PSC is largely
rectifying (contains the virally expressed
construct) in the unpaired controls, the PSC
remains wildtype (little rectification little
surface expression of the virally exspressed
receptor)
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Fig. 4 Preventing surface expression of AMPA
receptors using a plasticity block construct
prevents auditory learning
Viral construct delivered component that did not
affect basal transmission but did prevent
activity-dependent appearance of AMPA Rs on the
surface and did block LTP. B Behavioral
testing paradigm to evaluate effects of the
plasticity blocking construct (C-tail) vs the
viral infection control (GFP). C The C-tail
blocking construct diminished learning measured
both 3 24 hrs later, compared to GFP control
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RESULTS Virally delivered gene constructs
allowed GluR1 mutant AMPA receptors to be
expressed locally in a fraction of amygdala
neurons. The receptors were trafficked to the
surface and participated normally in synaptic
function. If a construct was used that blocked
activity-dependent AMPA receptor trafficking to
the synapse, it prevented auditory fear
conditioning, a form of associative
learning. TAKEHOME The trafficking of AMPA
receptors to the synapse to generate LTP is
essential for at least some forms of learning and
memory.