Synaptic Efficacy
__________ can erase the increase in EPSP size due to LTP.
LTD
Describe how LTD occurs in the hippocampus.
LTD appears to result from the activation of phosphatases, specifically PP1 and PP2B (calcineurin), a Ca2+-dependent phosphatase. Just as LTP at this synapse is associated with insertion of AMPA receptors, LTD is often associated with a loss of synaptic AMPA receptors, most likely due to the internalisation of AMPA receptors into sorting endosomes in the postsynaptic cell via clathrin-dependent endocytosis. As is also the case for LTP, there is a late phase of LTD that requires synthesis of new proteins.
What accounts for the input specificity of LTP?
The fact that the postsynaptic Ca2+ signals are highly localised.
What has cerebellar LTD been implicated in?
This form of LTD has been implicated in the motor learning that mediates the coordination, acquisition and storage of complex movements in the cerebellum.
Define supra-threshold.
(Of a stimulus) large enough in magnitude to produce an action potential in an excitable cell.
Describe how extra AMPA receptors are added to the postsynaptic synapse during LTP.
. It is thought that CaMKII and protein kinase C (PKC), both activated by the postsynaptic rise in Ca2+, phosphorylate downstream targets, including AMPA receptors, which collectively facilitate delivery of extrasynaptic AMPA receptors to the synapse, thereby enhancing the postsynaptic response to glutamate released from the presynaptic terminal.
What was a key advance in the elucidation of the mechanisms underlying LTP?
A key advance in the elucidation of the mechanisms underlying LTP was the discovery that antagonists of NMDA-type glutamate receptors prevent LTP during high-frequency stimulation of Schaffer collaterals, but have no effect on the synaptic response evoked by low-frequency stimulation.
How is cerebellar LTD associative?
Cerebellar LTD is associative because it only occurs when climbing fibres and parallel fibres are activated at the same time.
What does the vesicle depletion hypothesis say?
According to the vesicle depletion hypothesis, depression reduces the strength of transmission until the pool is replenished by mobilisation of vesicles from a reserve pool; further depression occurs when the size of the reserve pool is reduced - e.g. by impairing synapsin, a protein involved in the maintenance of vesicles in the reserve pool.
Describe how synaptic facilitation arises?
Although the entry of Ca2+ into the presynaptic terminal occurs within 1 to 2 milliseconds after an action potential invades, the mechanisms that return Ca2+ to resting levels are much slower. Thus, when action potentials arrive close together in time, calcium builds up in the terminal and allows more neurotransmitter to be released by a subsequent presynaptic action potential. Recent evidence indicates the target of this residual Ca2+ signal is synaptotagmin 7, a Ca2+-binding protein on the plasma membrane.
What is post-tetanic potentiation, and when does it occur?
As a result of its slow time course, potentiation may outlast the tetanic stimulus that is inducing it, in which case it is called post-tetanic potentiation (PTP).
Where has long-term synaptic plasticity been most thoroughly studied?
At excitatory synapses in the mammalian hippocampus.
What prevents LTP measured several hours after a stimulus, without affecting LTP measured at earlier times?
Blocking protein synthesis.
How do synaptic potentiation and augmentation arise?
Both augmentation and potentiation are thought to arise from prolonged elevation of presynaptic calcium levels during synaptic activity, although the mechanisms involved in this are poorly understood. It has been suggested that augmentation results from Ca2+ enhancing the actions of the presynaptic SNARE-regulatory protein munc-13, while potentiation may arise when Ca2+ activates presynaptic protein kinases responsible for the phosphorylation of substrates involved in transmitter release.
In hippocampal preparations, the cell bodies of the pyramidal neurons lie in a densely packed layer that is divided into several distinct regions, including __________ and __________.
CA1 CA3
What is the full name of CamKII?
Ca2+/calmodulin-dependent protein kinase type II.
What is the most abundant postsynaptic protein at Schaffer collateral synapses?
CaMKII.
Describe how LTD is brought about in the cerebellum.
Cerebellar LTD is associative because it only occurs when climbing fibres and parallel fibres are activated at the same time. Two distinct intracellular signal transduction pathways are activated in the postsynaptic Purkinje cell in response to activity in the climbing and parallel fibres. In the first pathway, glutamate released from parallel fibres activates AMPA-type and metabotropic receptors. Glutamate binding to the AMPA receptor results in mild membrane depolarisation, whereas binding to the metabotropic receptor produces the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). In the second pathway, glutamate released from climbing fibres activates AMPA receptors, strongly depolarising the Purkinje cell membrane potential, initiating the influx of Ca2+ through voltage-gated channels. IP3 and Ca2+ cause an amplified rise in intracellular Ca2+ by acting together on IP3 receptors, releasing Ca2+ from the endoplasmic reticulum. This is followed by the synergistic activation of PKC by Ca2+ and DAG. In this way, IP3 receptors and PKC serve as coincidence detectors. What are coincidence detectors? Other protein kinases act to sustain the activation of PKC as IP3 and Ca2+ concentrations begin to fall. PKC phosphorylates several downstream substrate proteins, including AMPA receptors, leading to the internalisation of AMPA receptors via clathrin-mediated endocytosis. This loss of AMPA receptors reduces the response of the postsynaptic Purkinje cell to glutamate released from the presynaptic terminals of the parallel fibres. CREB appears to be required for a late phase of cerebellar LTD, although it is not yet known which proteins are synthesised as a consequence of CRE activation.
Purkinje neurons in the cerebellum receive two distinct types of excitatory input, from which fibres?
Climbing fibres and parallel fibres.
LTD occurs if what is repeated (temporal)...
If the order is reversed, so that the postsynaptic neuron is excited before the presynaptic neuron, and this is repeated, LTD results.
How long does it take for synaptic facilitation to decay?
Facilitation decays over a time course of tens of milliseconds.
Give four forms of short-term synaptic plasticity.
Facilitation. Depression. Potentiation. Augmentation.
True or false: LTP has only been discovered at excitatory synapses in the hippocampus of the mammalian brain.
False: LTP has also been observed at excitatory synapses in a variety of brain regions, including the cortex, amygdala, and cerebellum - in addition to inhibitory synapses.
What effect does electrical stimulation of the Schaffer collaterals have on the CA1 pyramidal neurons?
If the Schaffer collaterals are stimulated only two or three times per minute, the size of these EPSPs remains constant. However, a brief, high-frequency train of stimuli to the same Schaffer collaterals causes LTP, which is evident as a long-lasting increase in EPSP amplitude. In some cases, this can last for over a year.
What is true of the arrangement of neurons in the hippocampus?
It allows the hippocampus to be sectioned such that most of the relevant circuitry remains intact.
Discuss insertion of receptors during LTP.
LTP results from synaptotagmin-mediated insertion of AMPA receptors into the post-synaptic membrane. These AMPA receptors come from an intracellular organelle known as the recycling endosome. The resulting increase in the density of AMPA receptors increases the response of the postsynaptic cell to released glutamate, yielding a strengthening of synaptic transmission. LTP does not affect the number of postsynaptic NMDA receptors; thus, while these receptors are crucial for the induction of LTP, they do not play a major role in LTP expression. AMPA receptors may even be added to "silent" synapses, previously devoid of such receptors. Under some circumstances, LTP can also increase the ability of presynaptic terminals to release glutamate.
Describe how LTP and LTD are kind of similar but also different.
Like LTP, LTD requires activation of NMDA-type glutamate receptors and the resulting entry of Ca2+ in the postsynaptic cell; small and slow rises in Ca2+ lead to depression, while large and fast increases in Ca2+ trigger potentiation.
What does LTD stand for?
Long-term depression.
What does LTP stand for?
Long-term potentiation.
Which piece of evidence suggests depression depends on the amount of transmitter that has been released?
Lowering the external Ca2+ concentration, to reduce the number of quanta released by each presynaptic action potential, causes the rate of depression to be slowed.
What does PTP stand for?
Post-tetanic potentiation.
How is is thought that STPD is brought about?
Specifically, if a postsynaptic action potential occurs after presynaptic activity, the resulting depolarisation will relieve the block of Mg2+ and cause a relatively large amount of Ca2+ influx through postsynaptic NMDA receptors, yielding LTP. In contrast, if the postsynaptic action potential occurs before the presynaptic action potential, then the depolarisation associated with the postsynaptic action potential will subside by the time an EPSP occurs, reducing the amount of Ca2+ entry through NMDA receptors (how?), leading to LTD.
What does STDP stand for?
Spike timing-dependent plasticity.
How are the CA1 and CA3 pyramidal neurons connected?
The dendrites of the CA1 pyramidal neurons receive synaptic inputs from Schaffer collaterals, the axons of CA3 pyramidal neurons. Electrical stimulation of Schaffer collaterals generates EPSPs in the postsynaptic CA1 pyramidal neurons.
Describe how LTP is initiated (up to Ca2+ entry).
The NMDA receptor channel is permeable to Ca2+ but is blocked by Mg2+ at the normal resting membrane potential. During low-frequency synaptic transmission, glutamate released by the Schaffer collaterals binds to both NMDA-type and AMPA-type glutamate receptors, but Mg2+ blocks the flow of current through the NMDA receptors, so that the EPSP is mediated entirely by the AMPA receptors. However, summation of EPSPs during high-frequency stimulation leads to a prolonged depolarisation that expels Mg2+ from the NMDA channel pores, allowing Ca2+ to enter the dendritic spines of postsynaptic CA1 neurons (through NMDA channels). The Ca2+ entry triggers LTP.
Describe the later phase of LTP.
The later phase of LTP appears to be initiated by protein kinase A (PKA), which activates transcription factors, such as CREB, responsible for upregulating the expression of other important proteins - while many of these proteins are unknown, they include other transcriptional regulators, protein kinases and AMPA receptors. There is also evidence that the number and size of synaptic connections increase during LTP, so it is thought many of these proteins may be involved in the construction of new synaptic contacts.
What causes dynamic changes to the strength of a peripheral neuromuscular synapse in the post-tetanic phase?
The varying timescales over which the short-term plasticity mechanisms decay.
Which lines of evidence indicate that facilitation is the result of prolonged elevation of presynaptic calcium levels following synaptic activity?
The postsynaptic membrane potential (excitatory post-synaptic potential) shows greater depolarisation in response to a presynaptic action potential when it has been previously depolarised in response to another, recent presynaptic action potential - i.e. the second EPSP is larger than the first. The smaller the interval between the stimuli (on the millisecond level), the greater the amount of facilitation.
What can also be an important determinant of the amount and direction of long-term synaptic plasticity?
The precise temporal relationship between activity in the pre- and postsynaptic cells.
There is evidence that STDP is important for what?
There is evidence that STDP is important for neural circuit function, such as determining orientation preference in the visual system.
How does synaptic depression arise?
These findings suggest depression is caused by the progressive depletion of a pool of synaptic vesicles that are available for release; when rates of release are high, these vesicles deplete rapidly and cause a large amount of depression; when rates of release are slow, vesicles are more readily available, and depression is reduced.
True or false: LTP and LTD are specific to the activated synapses.
True.
True or false: LTP reduces the strength of transmission at cerebellar synapses with both climbing and parallel fibres.
True.
True or false: Multiple mechanisms can result in LTP and LTD.
True.
When does synaptic facilitation occur?
When two or more action potentials invade the presynaptic terminal within a few milliseconds of each other.
What causes LTD?
Whereas LTP at the Schaffer collaterals and the CA1 pyramidal cells in the hippocampus requires brief, high-frequency stimulation, LTD occurs when the Schaffer collaterals are stimulated at low frequencies for long periods (10-15 minutes).
What is the difference in time course between synaptic augmentation and potentiation?
While augmentation operates over a few seconds, potentiation acts over a timescale of tens of seconds to minutes.
The total amount of synaptic depression is proportional to...
the amount of transmitter released from the presynaptic terminal.
LTP will occur if the following procedure is completed (temporal)...
the postsynaptic neurone is stimulated to cause an action potential superimposed over an EPSP caused by an earlier presynaptic action potential.
