Lecture 9 - Chapter 8: Synaptic plasticity Flashcards
Name examples of:
- Immediate memory
- Working memory
- Long-term memory
- Immediate memory → someone says the number 9 and you immediately store this memory for a couple of seconds.
- Working memory → keeping information for a short period of time, for instance when you lost your key around the house and are looking for it (you don’t remember this for the rest of your life)
- Long-term memory → can be reached when rehearsal takes place.
What’s the importance of synaptic plasticity?
It’s important for remembering and memory
What is short-term plasticity?
Short term plasticity is short term communication between neurons through synapses, which is triggered by the release of calcium (facilitation) and results in the release of neurotransmitters.
The fact that calcium levels instantly rise, but do not instantly decay, gives rise to plasticity (augmentation and potentiation).
What is long-term plasticity?
This is plasticity that lasts for more than 30 minutes. This is dependent on NMDA receptor-dependent calcium influx. Calcium changes the properties of synapses (post-translational modifications), which also affects gene expression and protein synthesis.
There are three different forms of short-term plasticity. Name and explain these.
- Facilitation → enhances synaptic transmission for tens of milliseconds.
- Augmentation → enhances synaptic transmission for a few seconds.
- Potentiation → enhances synaptic transmission for tens of seconds to minutes.
What is paired-pulse facilitation?
Here, postsynaptic potentials evoked by an impulse are increased when that impulse closely follows a prior impulse. This is due to the fact that during short-term plasticity, there’s instant rise of calcium and slow decay. So when the second impulse closely follows the first impulse, there’s still residual calcium that can enhance the second postsynaptic potential.
So when does paired-pulse facilitation decay?
When the intervals between stimuli increase.
What’s the opposite of faciliation?
Short-term depression
What happens during short-term depression and how does it occur?
Short-term depression decreases the amplitude of postsynaptic potentials. It is a result of the decrease in ready releasable pools of vesicles as a result of frequent stimulation.
What is seen during stimulation?
That it is an interplay between facilitation and depression (will become more clear in the following questions).
What happens when there’s high frequency stimulation in the following situations:
- Normal [Ca2+]
- Low [Ca2+]
- Intermediate [Ca2+]
- High frequency stimulation in normal [Ca2+] concentrations leads to synaptic depression, due to the release of almost all readily releasable pools.
- High frequency stimulation in low [Ca2+] concentrations leads to synaptic augmentation. This is because, there’s not enough calcium to release/deplete all the readily releasable pools.
- High frequency stimulation in intermediate [Ca2+] concentrations leads to both synaptic augmentation as depression. This happens, because there’s enough Ca2+ to stimulate the secretion of readily releasable pools, but this eventually will lead to the depletion of the pools (only less rapid compared to a normal [Ca2+] concentration.
Summarizing the previous questions:
Explain what happens during short-term plasticity upon stimulation.
Stimulation starts with paired-pulse facilitation (augmentation), which increases the postsynaptic membrane potential. At some point, the readily releasable pools are depleted. This leads to depression.
When the stimulation ends, there is still residual calcium available in the synaptic cleft (due to slow decay). This ultimately leads to post-tetanic potentiation.
Researchers won the Nobel prize for a certain experiment they performed in the gill of Aplysia. What was researched?
The gill of Aplysia has a withdrawal reflex. So if the siphon was touched, it pulled back/contracted its gill. So they started performing experiments on Aplysia to see what would happen to the magnitude of gill contraction when the siphon was touched in multiple trials.
What did they see during the experiment of Aplysia and the magnitide of gill contraction after touch?
That in the first trial where they touched the siphon, they still measured a high amplitude of gill contraction. But after a few trials (> trial 6) the magnitude of gill contraction began to decrease. At trial 13, there was almost no magnitude of gill contraction measured. So habituation occurred.
What happens to the amplitude of gill contraction after giving a shock to the tail of the Aplysia and simultaneously touching the siphon?
Sensitization occurs, which is the progressive amplification of a response due to (repeated) administration of a stimulus.
What’s seen here?
Short-term memory.
- You see that when the stimulus (touching siphon) is given several times, the amount of response to the stimulus decreases (black lines).
- You see that when a single tail shock is given, the response to this stimulus first increases (habituation). But if you repeat this several times, also the response to the tail shock will decrease again (sensitization).
How do you go from short-term sensitization/memory to long-term sensitization?
By shocking the tail repeated times for several days, as can be seen in the picture.
Describe what happens in the neurons of Aplysia during short term sensitization.
Touching the siphon skin activates a sensory neuron. This neuron releases glutamate onto a motor neuron. The motor neuron release acetylcholine to the muscle of the gill, which leads to contraction of the gill.
What happens when there’s habituation of the neuronal system responable for the contraction of the gill in response to frequent stimulation by touch?
There’s less response to the stimuli, therefore the sensory neuron sents less signals to the motor neuron and the amplitude of contraction is decreased.
Describe what happens when the tail of Aplysia is stimulated with a shock.
The tail is connected to a sensory neuron. This neuron is connected to a modulatory interneuron, that has connection with the sensory neuron of the siphon skin and the motor neuron that is connected to the gill.
When the tail is stimulated, signals are sent through the sensory neuron to the modulatory interneuron. Unlike most interneurons, this modulatory interneuron is excitatory and excites the interneuron and motor neuron that have been habituated by touching the siphon skin.
To summarize:
What neurotransmitters are produced by the modulatory interneuron, sensory neuron and motor neuron?
- Interneuron → serotonin
- Sensory neuron → glutamate
- Motor neuron → acetylcholine
Describe what happens inside (referring to intracellular signal cascades) the neurons of Aplysia during short term sensitization.
- Stimulating the tail Aplysia with shock
- Sensory neuron produces glutamate
- Glutamate activates modulatory interneuron
- Interneuron produces serotonin
- Serotonin receptor activation on sensory neuron
- Production of cAMP, activation of PKA
- Reduces K+ channel activation
- AP mediated effect prolonged
- Increased Ca2+ influx
- Enhanced glutamate release from sensory neuron → enhanced motor neuron activation → enhanced ACh release
- Enhanced gill contraction
What does short-term sensitization depend on and what does long-term sensitization depend on?
- Short-term sensitization → PKA-dependent enhancement
- Long-term sensitization → CREB-dependent gene expression
Describe what happens inside (referring to intracellular signal cascades) the neurons of Aplysia during long-term sensitization.
- Stimulating the tail Aplysia with shock
- Sensory neuron produces glutamate
- Glutamate activates modulatory interneuron
- Interneuron produces serotonin
- Serotonin receptor activation on sensory neuron
- Production of cAMP, activation of PKA
- PKA activates CREB
- CREB increases gene transcription
- Transcription of ubiquitin hydrolase further activates PKA
- CREB also activates C/EBP → C/EBP activates genes responsible for adding more synapses.
Describe the pathway in the brain during long-term potentiation at hippocampal synapses.
Information goes from the preforant path to the granule cells of the dentate gyrus. The axons of the granule cells (mossy fibers) activate CA3 pyramidal cells. The axons of CA3 pyramidal cells (Schaffer collaterals) activate CA1 pyradimal cells.
How can you measure long-term potentiation in the lab?
By stimulating the axons of CA3 pyramidal cells (Schaffer collaterals) that connect to CA1 pyramidal cells, so that the excitatory postsynaptic potential (EPS) of CA1 pyramidal cells can be measured.
This can be done by using two electrodes on two different axons of CA3 pyramidal cells.
- The first stimulus on the first axon is a normal stimulus (control) and results in ‘normal’ EPS.
- The second stimulus on the second axon is a high frequency stimulus, which causes a rapid increase in EPS. When you stop the high frequency stimulus, you see that the EPS doesn’t go down immediately. Here, long-term potentiation can be seen/measured.
How long can this long-term potentiation last?
It can last for a year, as can be seen in the picture.
What can be seen when the presynaptic activity is simultaneously paired with postsynaptic activity (presynaptic release of NT at the same time as postsynaptic potential)?
State dependency can be measured. This is a mechanism that allows for a connection to be strenghtened, only when the presynaptic activity is coincident with the postsynaptic depolarization.
What is meant with specificity and associativity in long-term potentiation?
- When you strongly stimulate one of the axons, while weakly stimulating the other axon, the synapse of the axon that is weakly stimulated will not strenghten (so no long-term potentiation). This, while the axon that is strongly stimulated, results in strenghtening of the synapse (specificity)
- But, long-term potentiation caused by strong stimulation of the axon, does initiate LTP in nearby weakly active synapses when the weak stimulus is coincident with activation of the postsynapse. Therefore, weak stimulation in combination with coincident postsynaptic activity, will result in strenghtening of the synaps (associativity).
Neurons that fire together, wire together.
Consider that you have a “go to the toilet neuron” and a bladder neuron, where the synapse between the “go to the toilet neuron and the bladder neuron is still weak.
How can you ensure that when the bladder is full, this stimulus is associated with the “go to the toilet neuron”?
By using a stronger synaptic connection, like using candy to associate it with going to the toilet when your bladder is full.
So if you give a child candy before going to the toilet, the synaptic connection between the bladder and the “go to the toilet neuron” is strengthened.
(If you don’t understand this, make sure you understand the previous two questions about specificity and associativity).
What’s seen in Alzheimer’s patients when long-term potentiation is induced?
That long-term potentiation is affected by amyloid-beta.
How is short-term potentiation initiated in hippocampal synapses?
- When the presynaps is depolarized and glutamate-filled vesicles are released into the synaptic cleft, glutamate can bind to AMPA and NMDA receptors.
- Na+ then flows into the postsynaptic cell through AMPA, which causes postsynaptic depolarization. This releases the Mg+ block on the NMDA receptor and calcium and sodium can flow into the postsynaptic cell via the NMDA receptor.
- Calcium can then initiate short-term potentiation via activation of calmodulin kinase 2 and PKC.
- Activation of these kinases leads to the insertion of extra AMPA receptors on the postsynaptic membrane.
How does NMDA receptor activation explain associativity?
When glutamate is presynaptically released into the synaptic cleft, it is able to bind to NMDA and AMPA receptors. This activates the AMPA receptor, but not the NMDA receptor since the NMDA receptor still has a Mg+ block. This Mg+ block can only be released if the postsynaptic membrane is depolarized by incoming sodium via the AMPA receptor. So you need some form of (weak) stimulation by glutamate to depolarize the postsynaptic membrane, so that you also can activate NMDA receptor.
How is long-term potentiation initiated in hippocampal synapses?
- When the presynaps is depolarized and glutamate-filled vesicles are released into the synaptic cleft, glutamate can bind to AMPA and NMDA receptors.
- Na+ then flows into the postsynaptic cell through AMPA. And when the Mg+ block is released on the NMDA receptor, calcium and sodium can flow into the postsynaptic cell via the NMDA receptor.
- Calcium can then initiate long-term potentiation via activation of calmodulin kinase 2 and PKC.
- Calmodulin kinase 2 (CaMKII) phosphorylates CREB and CREB can then translocate to the nucleus to activate gene transcription.
So activation of calmodulin kinase 2 leads to the activation of CREB, which leads to the transcription of genes. What does transcription of certain genes lead to?
More synaptic connections (synapse growth and additional synapses) and novel postsynaptic spines.
What happens when the stimulus that is given to this axon is low frequency (instead of high frequency stimulation as was discussed before) and after 15 minutes you give a second (normal) action potential?
Long-term depression occurs.
How/why does long-term depression occur when you give a low frequency stimulus?
The main player is still calcium. But sinds you give low frequency stimulation, the concentration of calcium is much lower. Instead of kinases being activated, now phosphatases are activated. These proteins dephosphorylate proteins, which results in:
- It makes AMPA receptors more mobile, which makes them have the tendency to leave the postsynaptic density and become endocytosed. This decreases the concentration of AMPA receptors on the spine.
