BIPN 140: Cellular Neurobiology

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BIPN 140 Cellular Neurobiology LECTURE 12
Synaptic Plasticity II
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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Fig 8.11 Signaling mechanisms underlying LTP
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Fig 8.12a Addition of postsynaptic AMPA
receptors during LTP
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Fig 8.12b Addition of postsynaptic AMPA
receptors during LTP
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Fig 8.12c Addition of postsynaptic AMPA
receptors during LTP
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Fig 8.13 Role of protein synthesis in
maintaining LTP
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Fig 8.14a Mechanisms causing synaptic change in
LTP
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Fig 8.14b/c Mechanisms causing synaptic change
in LTP
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Box 8Ba/b Silent Synapses
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Box 8Bc/d Silent Synapses
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Fig 8.15a/b Long-term synaptic depression in the
hippocampus
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Fig 8.15c Long-term synaptic depression in the
hippocampus
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Fig 8.16a LTD in the cerebellum
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Fig 8.16b LTD in the cerebellum
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Fig 8.16c LTD in the cerebellum
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Fig 8.16d LTD in the cerebellum
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Fig 8.17a Spike timing-dependent synaptic
plasticity in cultured hippocampal neurons
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Fig 8.17b Spike timing-dependent synaptic
plasticity in cultured hippocampal neurons
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Fig 8.c Spike timing-dependent synaptic
plasticity in cultured hippocampal neurons
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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.