NESC 2570 Lecture Notes - Lecture 9: Protein Kinase A, Adenylyl Cyclase, Excitatory Synapse
Why neural plasticity is important
While nervous systems control behaviour, originally, behaviour is maladaptive
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An organism that cannot adapt their behaviour will essentially perish
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They need to benefit from plasticity - survival of the fittest
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Neural plasticity includes behavioural modification but also includes changes that occur during
development and what the nervous system can deal with in regards to disease
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The way that we look at the world is shaped by our experiences as we grow up
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If we want to understand our psyche, we need to understand how they are formed and where they
come from
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Commonalities of neural plasticity
We consider synaptic plasticity to be a solid foundation of memory
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Forms of synaptic plasticity
The shortest time scale of forms of synaptic plasticity that last 10's of hundreds of milliseconds
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Synaptic Facilitation: refers to the phenomenon illustrated in the bottom image - two action
potentials that occur in rapid succession and the response to the second equal action potential
evokes a larger post synaptic response
The organism should display a more robust response
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Enduring changes in neural plasticity is the basis of our long lasting memory
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Magnitude of facilitation depends on the separation between the action
potentials
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Changing the extracellular solution bathing synapse
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Synapses can also manifest depression which is essentially the opposite of facilitation
The second action potential response (depolarization) is smaller than the original
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A train of action potential at high frequency can go down and the synapse will be depressed
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If you reduced the extracellular calcium concentration, this depression can be eliminated and the
response can be replaced with a facilitation
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As you reduce the calcium levels, the height of the post synaptic response will be lower due to less
release of the vesicles
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The cause of the depression due to trends is a depletion of the readily releasable pool of vesicles
It takes time before more vesicles can be docked and prepare to be released, until this
happens then there can be no release
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If the action potential is unreliable, then depression won't happen right away, the little bit of
calcium that came in with the first action potential may still be present. So the concentration of
calcium will build up and be able to facilitate another action potential and achieve success
It only lasts for a very short time because synapses can efficiently get rid of extracellular
calcium
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Depression manifesting itself when the pool is exhausted also counts for the phenomenon
that the depression relies on the synapse
Particularly for mammalian synapses, transmitter release is NOT a guaranteed thing
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Neurotransmission commonly is unreliable, an action potential will not always revoke
transmitter release and thus post synaptic response
Usually, a stimuli will have a given probability of triggering an action potential
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Amount of depression relies on the relative amount of transmitter release (reliability of the
synapse)
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After some initial depression, long enough to let the synapse to restock its vesicles, the
low frequency stimulation will elicit a larger response than the original - this is referred
to Post Tetanic Potentiation (PTP)
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PTP is observed at almost all synapses and it lasts 10's of seconds before subsiding to
baseline
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There is also an intermediate form that doesn't last as long which is referred as
augmentation
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This phenomena cannot be due to the calcium in the pre synaptic terminal because there
is non-during extended periods of time after action potential
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Protein Kinases and phosphatases that are activated by elevated calcium
Molecules such as Munc13 and synapsin and possibly account for these
phenomena
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These longer term phenomena forms plasticity can
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All these phenomena can happen subsequently
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Unlikely candidates for learning and memory due to their relatively short duration
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Faced with the problem of only lasting for a certain amount of time
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Plisia - sea hare
Their ganglia were the elements of their CNS, the ganglia had low numbers of neurons (a
few hundred) and they contained many large, reproductifyable cell
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Can always find the same cell by virtually the same location and identical connections
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This is awesome for scientists because they can replicate their findings and establish
confidence
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Look at the reflex they show when they are sitting undisturbed in the water, it has a gill
that it sends out that is irrigated by passing water currents and allows the sea hare to
breathe
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The gill is a critical structure but it is also very delicate
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If you touch them on the siphon, they will rapidly withdraw their gill - if you do this in
rapid succession it will exhibit habituation
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Weaker and weaker withdraw - assuming the animal is
learning that the touch isn't threatening, so why waste
energy
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Habituation is common in the nervous system - ex. When
you put a shirt on in the morning after sleeping and you
acknowledge the stimuli of the cold sadness of having to get
out of bed and face responsibilities
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Sensitization is when there was a previous habituation but
following the pairing of the stimulus with a strong stimulus
and the habituation is replaced
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Sensitization doesn't decay and can last for hours
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If you gave not one pairing of the inocculus stimuli with a shock, but a
series of them, then a subsequent application of the stimuli alone will
robustly withdrawal for many days, even weeks
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We have now experienced a form of plasticity that is lasting long enough
for short term memories to be made of
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Simple network of neurons responsible of sensitization
Synapses made by the sensory neurons that probe the siphon skin
which goes to the sensory neuron to trigger the interneuron to the
motor neuron and elicit a response
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Sensory neurons make synapses on a number of interneurons on the
ganglion
Some of these interneurons make additional - the synapses onto
the synapse made by the siphon skin neuron onto the motor neuron
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That synapse is a presynaptic synapse - the interneuron is making
contact with the presynaptic terminal of the sensory neuron
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Action potentials that are evoked artificially in the sensory neuron and the motor neuron
responses are documented
Repetition of the single action potentials which is a consequence of the number of
phenomena and the activation of the interneuron
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After the pairing of the electrical activation of the sensory neuron with the strong stimulus
of the tail nerve (bundle of fibers including a sensory neuron) the reduced preparation can
evoke sensitization
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Stimulation of the tail nerve evokes a large response - single cell correlate of the
behavioural sensitization
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They found that the activation of the interneuron influenced the behaviour of the sensory terminal
synapsing on the motor neuron
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Modulatory interneuron found to be a serotonergic neuron
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The receptors to serotonin are metabotropic receptors and their consequence is to activate adenylyl
cyclase which leads to an increase in cAMP levels in the presynaptic terminal
cAMP is a very important second messenger and when it's levels are increased, they activate
Protein Kinase A and that works by cAMP binding to modulatory subunits and they then
dissociate from catalytic subunit which activates them
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PKA can then phosphorylate the substrate - when the voltage gated potassium channels, they
become less active which causes the repolarization to cease to occur or at least slow down, so
we have a longer calcium channel opening and more release
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This is how the synapse becomes sensitized - after the release of serotonin, the action potential in
the sensory neuron is more effective in releasing transmitter
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When the cAMP levels are raised and they are raised for an extended period of time, that
can lead to the activation by phosphorylation mediation of protein kinase A
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PKA can phosphorylate a transcription factor present in the terminal but when
phosphorylated get transported back to the nucleus and can bind to cAMP - it increases the
transcription and translation of genes
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Consequence of strong activation of PKA mediated by phosphorylation transcription
factor will change gene expression - general mechanism in long lasting memory
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Degregation - nothing left to activate catalytic subunits #wat
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Among the activated genes, must be some of the structural genes of growth in synapse
formation - raises the possibility that memories involve not just alteration in biochemical
but also in physical changes
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These phenomena identified in the sea hare were able to be generalized -
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Possible to identify by simple learning paradigms for dumbass fruitflies - many mutations interfere
with learning abilities and these mutations involve the cAMP pathway
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Failure along with investigations have led to the conclusion of the phenomena that are central to
long lasting neural plasticity is not reliable for mammalian processes
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LTP is observed in every excitatory synapse in the brain and is widely accepted to be part of the
long term learning machinery
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Long lasting forms of synaptic changes which can be the possible cellular leads to long term
memory
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LTP stands for Long Term Potentiation
Long Term Depression which is the long term synaptic weakening of connections (LTD)
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LTP is studied in mammalians because we need to have something that is applicable to humans so
#byefruitflies
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Hippocampus - specific memory structure in the brain
HM had a portion of his hippocampus removed and he was unable to create new memories
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Place cells - particular in the hippocampus that only fire an action potential when an animal is in a
certain position in the environment, therefore this is very important to spactial memory
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Bliss, Lomo and Andersen did studies on rabbits
You can slice the hippocampus in a specific way where the internal connections are still
intact
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The pyramidal cells form a densely packed singly layer that are readily identifiable
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They form a unidirectional circuit
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Inventro hippocampal slices are basically functioning hippocampi
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CA - refers to Cornu Ammon
CA1 and CA3
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The accents of CA3 cells are referred to Schaffer collaterals and they synapse onto CA1
pyramidal cells
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Plasticity
November(30,(2015
1:28(PM
Document Summary
While nervous systems control behaviour, originally, behaviour is maladaptive. An organism that cannot adapt their behaviour will essentially perish. They need to benefit from plasticity - survival of the fittest. Neural plasticity includes behavioural modification but also includes changes that occur during development and what the nervous system can deal with in regards to disease. The way that we look at the world is shaped by our experiences as we grow up. If we want to understand our psyche, we need to understand how they are formed and where they come from. We consider synaptic plasticity to be a solid foundation of memory. The shortest time scale of forms of synaptic plasticity that last 10"s of hundreds of milliseconds. Synaptic facilitation: refers to the phenomenon illustrated in the bottom image - two action potentials that occur in rapid succession and the response to the second equal action potential evokes a larger post synaptic response.