Download Short term plasticity

Neurobiology 2008
Micha Spira
Learning and Memory
The Aplysia Model
STF
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• Homosynaptic depression is the
electrophysiological equivalent of
habituation
• Dishabituation leads to increased Rin
(~140%) of the sensory neuron
• WHAT IS THE MECHANISM OF
INCREASED Rin ??????
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A New concept- neurotransmitter that
modulate channels conductances rather
than turn on ionic channels
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Figure 15-30 Molecular Biology of the Cell (© Garland Science 2008)
The structure of an inactive G protein
The units are
covalently linked to
lipids.
When activated it
operates as a
guanine nucleotide
exchange factor
(GEF)
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Figure 15-31 Molecular Biology of the Cell (© Garland Science 2008)
The new concept is that binding
to the receptor expose buried
surfaces rather than dissociate
between the subunits
The a subunit function as a
GTPase
The target or specific proteins
regulate by enhancing the
GTPase activity of the a
subunit
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Figure 15-32 Molecular Biology of the Cell (© Garland Science 2008)
cAMP concentration is 10-7, an extracellular signal can increase
the concentration within seconds by a factor of 20.
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Figure 15-33 Molecular Biology of the Cell (© Garland Science 2008)
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Figure 15-34 Molecular Biology of the Cell (© Garland Science 2008)
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Table 15-1 Molecular Biology of the Cell (© Garland Science 2008)
• Cholera toxin- inhibit the GTPase activity,
leads to elevated cAMP levels , that cause
release of Cl and water from epithelial
cells to the gut.
• Pertussis toxin prevents the protein fro
interacting with the receptors
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The activation of PKA (cyclic AMP
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Figure 15-35 Molecular Biology of the Cell (© Garland Science 2008)
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Figure 15-36 (part 1 of 2) Molecular Biology of the Cell (© Garland Science 2008)
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Neurobiology 2008
Micha Spira
PKC and STF Aplysia Model
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Non depressed synapse. Short term facilitation
5 minutes after 5HT application
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Inositol Phospholipid signaling
pathway
• GPCRs (Gq) also exerts their effects by
activation of the membrane bound
Phospholipids
• The substrate is a phosphorylated inositol
phospholipids PIP2 which is presented in
small amounts on the inner half of the
plasma membrane
• Cleavage of PIP2 gives diacylglycerol and
Inositol trisphosphate
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Figure 15-37 Molecular Biology of the Cell (© Garland Science 2008)
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Figure 15-38 Molecular Biology of the Cell (© Garland Science 2008)
Initiation and termination of the
signal
• IP3 is water soluble
• IP3 binds to IP3 gated calcium channels of
the ER and releases calcium.
• IP3 is inactivated by:
Dephosphorylation to IP2
IP3 is phosphorylated by a specific kinase to IP4
Ca is pumped out of the cell
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Diacylglycerol
• Lipid soluble operate at the interface of the
membrane
• Ca induce traslocation of PKC from the
cytosol to the plasma membrane. The
calcium in combination with diacylglycerol
activate PKC
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Figure 15-39 Molecular Biology of the Cell (© Garland Science 2008)
Fertilization of an egg by a sperm
The penetrating sperm releases PLC which induces release of calcium
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Figure 15-40 Molecular Biology of the Cell (© Garland Science 2008)
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Figure 15-41a Molecular Biology of the Cell (© Garland Science 2008)
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Figure 15-41b Molecular Biology of the Cell (© Garland Science 2008)
Calmodulin acts as a
multipurpose intracellular calcium
receptor
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Figure 15-43 Molecular Biology of the Cell (© Garland Science 2008)
Calmodulin activates CaM- Kinase II
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Figure 15-44 Molecular Biology of the Cell (© Garland Science 2008)
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Alterations at the post synaptic
level
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Figure 15-45 Molecular Biology of the Cell (© Garland Science 2008)
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Amplification and time scales
• A single molecule of rhodopsin activated by a
single photon catalyze the activation of
hundreds of transducine at a rate of about
1000 transducins / sec
• Each transducin activate phosphodiesterase that
hydrolyze 4000 cGMP/ sec.
• The cascade lasts 1sec
• This leads to closure of hundreds of cataion
channels in the membrane
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Long term potentiation
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Micha Spira
Neurobiology 2008
• Long term
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Figure 15-36 Molecular Biology of the Cell (© Garland Science 2008)
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Figure 15-36 (part 2 of 2) Molecular Biology of the Cell (© Garland Science 2008)
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Activation of nuclear transcription
factor
• cAMP responsive element
• CRE –binding protein (CREB1) phosphorylated
by PKA, MAPK or Cam kinase
• CREB1 function as transcriptional activator
• Leads to LTF
• Injection of CRE oligonucleotides binds to
CREB1 and block LTF but not STF
• Concomitantly CREB2 is down regulated by
MAPK
• Injection of antiCREB2 antibodies is sufficient to
trigger facilitation
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Aplysia sensory neurons
Fig. 2. Time course and functional contribution of two distinct presynaptic structural changes associated with intermediate- and
long-term facilitation in Aplysia. Repeated pulses of 5-HT in sensory to motor neuron co-cultures trigger two distinct classes
of presynaptic structural changes: (1) the rapid clustering of synaptic vesicles to pre-existing silent sensory neuron varicosities
(3–6 h) and (2) the slower generation of new sensory neuron synaptic varicosities (12–18 h). The resultant newly filled and newly
formed varicosities are functionally competent (capable of evoked transmitter release) and contribute to the synaptic enhancement
that underlies LTF. The rapid filling and activation of silent presynaptic terminals at 3 h suggests that, in addition to its role
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in LTF, this modification of pre-existing varicosities may also contribute to the intermediate phase of synaptic plasticity. Red
trianglesrepresent transmitter release sites (active zones). (Modified from Kim et al., 2003.) (See Color Plate 10.2 in color plate
Fig. 3. Regional specific down-regulation of the
transmembrane isoform of apCAM. This model is
based on the assumption that the relative
concentration of the GPI-linked versus
transmembrane isoforms of apCAM is highest at
points of synaptic contact between the sensory
neuron and motor neuron and reflects the results of
studies done in dissociated cell culture. Thus,
previously established connections might remain
intact following exposure to 5-HT since they would be
held in place by the adhesive, homophilic interactions
of the GPIlinked isoforms and the process of
outgrowth from sensory
neuron axons would be initiated by down-regulation
of the transmembrane form at extrasynaptic sites of
membrane apposition. In the intact ganglion, the
axons of sensory neurons are likely to fasciculate not
only with other sensory neurons but also with the
processes of other neurons and perhaps even glia.
One of the attractive features of this model is that the
mechanism for down-regulation is intrinsic to the
sensory neurons. Thus, even if some of the sensory
neuron axonal contacts in the intact ganglion were
heterophilic in nature, i.e., with other neurons or glia,
we would still expect the selective internalization of
apCAM at the sensory neuron surface membrane at
these sites of heterophilic apposition to destabilize
adhesive contacts and to facilitate disassembly.(From
Bailey et al., 1997.) (See Color Plate 10.3 in color
plate
section.)
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Hippocampus
• 1- The neurotransmitter is glutamate
• Glutamate activate NMDAR leading to
increased free intracellular calcium
concentration.
• Ca /calmodulin stimulate postsynaptically
adenylyl cyclase.
• Increased AMPAR
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Synaptic capture of learning
induces gene products
• The activation of a specific synapse tag
the synapse
• Covalent modification
• Local protein synthesis to stabilize the
mark
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Local protein synthesis at active
synapse
• mRNA species are transported by special
mechanisms to the synaptic sites. They
are translated only after docking and in
response to a specific signal.
• 5x5HT at one synapse activate local
protein synthesis. If inhibited no LTF.
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Imaging of Alexa, synaptotagmin –
GFP, and synaptopHluorins
• 1- rapid activation of silent synapses by filling
empty varicosities by vesicles. The process
requires translation but not transcription. The
process is seen within 3-6 hr =intermediate
memory accounts for approximately 32% of the
new synapses.
• 2- generation of new varicosities requires
transcription and translation. Is seen only 12-18
hr after 5HT and accounts for 68% of the new
synapses
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Interesting to note
• Intermediate- uses pre existing structure in
which the presynaptic elements may be
already in register with post synaptic
receptors
• Long term requires more time to develop
the structure and to assemble both new
pre and post synaptic structures
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End of Aplysia Model
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