Lecture 13: Synaptic Strength and Short Term Plasticity Flashcards
What factors determine the magnitude of a PSP generated by a single presynaptic AP?
- availability of Ca2+
- presence of a toxin
How does the availability of Ca2+ affect the magnitude of a PSP generated by a single presynaptic AP?
less available Ca2+ (less enters presynaptic terminal) = less vesicles fusing (due to less synaptotagmin activated) = less neurotransmitter release = less response to receptors
How does the presence of toxins, particularly receptor antagonists, affect the magnitude of a PSP generated by a single presynaptic AP?
antagonists of receptors in the synapse affect the number of receptors available
less receptors = smaller response (even if the same amount of neurotransmitter is released)
Are postsynaptic voltage responses from a single synapse (ie. EPSPs) always the same size?
NO – they are variable in size
they are not always (or usually) sufficiently large to depolarize a postsynaptic neuron to threshold
What is synaptic strength?
relative size of the response in the postsynaptic neuron when the presynaptic neuron is stimulated with a stimulus of equivalent magnitude
What factors govern the magnitude of a PSP for a given stimulus?
- presynaptic factors
- cleft factors
- postsynaptic factors
- (other postsynaptic factors)
What are presynaptic factors?
how many quanta of neurotransmitter (ie. vesicles) are released for a given stimulation (number of APs)
What are cleft factors?
how rapidly neurotransmitters are broken down/removed from synaptic cleft
What are postsynaptic factors?
how many receptors are present at the PSD (and capable of binding neurotransmitter and generating currents)
What are other postsynaptic factors?
what subtype(s) of receptors are present – this affects the response due to:
- different transmitter binding affinities
- different response kinetics
- different ion selectivity
- different voltage sensitivity
- different conductance
What is synaptic plasticity?
ability of synapses to change their synaptic strength over time
synaptic plasticity = synaptic strength + plasticity
What does the quality of synaptic plasticity allow?
allows nervous system to adapt the ways in which it integrates and transfers information to better coordinate behaviour to the environment
What happens if synapses are used repeatedly?
changes their strength over short time scales
How is synaptic strength measured?
by peak amplitude, or (more often) rate of rise of the PSP (ie. change in amplitude for a given amount of time)
What happens to synaptic strength when stimulated by rapid repeated stimuli?
initially increases (facilitation)
but if the stimuli continue to occur, the strength decreases (depression)
How can you determine that synaptic plasticity (facilitation and depression) is occurring, rather than temporal summation occurring by itself?
temporal summation does not change the amplitude/rate of rise of the PSP (ie. synaptic strength)
True or False: synaptic plasticity only occurs when more than one synapse is activated
false
True or False: synaptic plasticity only occurs within the brain
false
True or False: temporal summation is the only thing that can occur if the PSPs overlap in time, so if you see overlap, there is no synaptic plasticity
false
Sometimes in synaptic plasticity, we use different terms to indicate separable processes (meaning processes that look superficially similar use different underlying biochemical mechanisms).
ie. terms that describe different biological processes that all create increases in synaptic strength, but persist for different amounts of time
- facilitation
- augmentation
- potentiation
Sometimes in synaptic plasticity, we use the same term to describe changes in synaptic strength that look similar, even though we know they also have different underlying mechanisms.
ie. the same word is used to describe decreases in synapse strength over different time-scales, even though these have different underlying mechanisms
- rapid depression
- short-term depression
- long-term depression
What is facilitation?
synaptic strength increases that last for ~10s of ms
What is augmentation?
synaptic strength increases that last for ~ 0.5 - 10s
What is potentiation?
describes synaptic strength increases that lasts ~ >30s
- short-term potentiation: up to ~30 min
- long-term potentiation: > ~60 min
What is rapid depression?
decreases in synapse strength that occur within ~10s of ms and last for up to ~1-10s
What is short-term depression?
decreases in synaptic strength that take longer to begin (1-10s) and last for 1-30 minutes
What is long-term depression?
decreases in synaptic strength that will last for > 60min once induced
What is short-term plasticity?
any use-dependent changes (changes in strength that occur by manipulating the history of activity of the synapse) in synaptic strength which occur over time scales up to ~10 min
When does short-term plasticity occur?
occurs when exposing a synapse to one or more stimuli transiently affects the strength of its response to stimuli that occur at later time points
What do characteristics of short-term plasticity (STP) depend on?
- type of stimuli
- type of synapse stimulated
How do different types of synapses (belonging to different neurons, or in different locations on the same neuron) differ?
show distinct patterns of short-term plasticity responses to a particular pattern of stimuli
What are 2 extra features used to categorize all forms of STP?
- frequency dependence
- temporal dependence
What is frequency dependence?
amount of change in synaptic strength varies based on the length of the interval between stimuli
(how much the interval between stimuli affects level of potentiation)
ie. in PPF example, varying the delay between the 2 stimuli leads to different amounts of increase in synaptic strength
What is temporal dependence?
amount (and direction) of change in synaptic strength varies based on how many stimuli have happened
(pattern of getting larger or smaller)
ie. in Katz’s example, the first 4-5 stimuli in the train produce augmentation, but as more stimuli occur, synaptic strength is then depressed below the original level
Do different synapses in CNS show characteristically different STP profiles to the same stimuli?
yes
What is paired pulse facilitation (PPF)?
form of short-term, use-dependent synaptic plasticity common to most chemically transmitting synapses, manifested as an enhancement in the amplitude of the second of two rapidly evoked excitatory postsynaptic potentials (EPSPs)
simplest example of short-term plasticity enhancing synaptic strength
How many stimuli is needed to see use-dependent short-term plasticity?
use-dependent short-term plasticity can be seen with as few as two consecutive stimuli
Synapses are usually either ______ OR ______ with PP stimuli.
depressing OR facilitating
What is the alternate framework that synaptic psychologists use to organize their questions about plasticity?
plasticity question framework
- direction
- maintenance
- expression
- induction
What is the direction question?
does the synapse become stronger or weaker
What is the maintenance question?
is the change stable over time, for how long, and what cellular mechanisms support long-term stability (or lability)
What is the expression question?
what is actually changing in the synapse to create a change in strength, and does it affect neurotransmitter release or receptor number or properties
What is the induction question?
what is the biochemical signal cascade that triggers the plasticity, and does it occur in the presynaptic or postsynaptic compartment
What is quantal content analysis?
refers to the measurement of PSP sizes under conditions when only a small number of vesicles would be released from a synapse per AP
- q: mean amplitude of a single quantum
- m: mean number of quanta released in a single trial
- m = n x p (number of vesicle release sites x probability of release of any vesicle by one stimuli)
- PSP: q x m
What has quantal analysis been used to demonstrate?
presynaptic location for PPF expression
- amplitudes of the PSPs for two consecutive stimuli (pulse 1 and 2) are measured
- size of q (mean amplitude of a single quantum) is unchanged from pulse 1 to pulse 2, but value of m (mean number of quanta released in a single trial) is increased
What does quantal analysis of short-term depression also often show?
evidence for presynaptic expression
example:
- synapse (in Aplysia sea slug) was repeatedly stimulated at low frequency (0.1 Hz) until it depressed (after ~100 stimuli – but you can see depression in some synapses for PP experiments)
- synaptic strength was monitored by quantal analysis
- after depression is induced, mean size of a quantum (q) remains the same, but release probability (p) decreases, and therefore mean quantal number (m) also decreases
What do we see at some synapses?
postsynaptic mechanisms of rapid short term depression (ie. PPD)
- postsynaptic response to the same amount of ‘puffed’ glutamate is reduced at short intervals compared to long intervals (at longer intervals, the response recovers back to close to its original size)
- this phenomenon is generally explained by receptor desensitization
What is receptor desensitization?
ionotropic receptors becoming inactivated after repeated openings within a short time and failing to respond to the new puff of neurotransmitter
A previous experiment showed evidence that in this synapse paired pulse depression is occurring because postsynaptic receptors are being briefly inactivated by the first stimulus. If you tried to perform quantal analysis on the PP ratio in this synapse, instead of testing the response to puffs of glutamate, what result would you predict?
reduction in q (quantal amplitude/content)
- if you do quantal analysis and see change in q, there are two possibilities – less receptors responding to the same amount of neurotransmitters, OR less neurotransmitters released
- very rare to see change in amount of neurotransmitter in vesicles
- change in q almost always says there has been a change in number of receptors available to respond
- change in q is usually a postsynaptically expressed change (change in synaptic strength based on changes in postsynaptic neuron)
Is a change in q (mean amplitude of a single quantum) usually a pre- or postsynaptically expressed change?
postsynaptically – change in synaptic strength based on changes in postsynaptic neuron
Is a change in facilitation expressed presynaptically or postsynaptically?
almost always expressed presynaptically
What causes rapid depression?
(depending on the synapse)
- q (mean amplitude of a single quantum)
- m (mean number of quanta released in a single trial)
What do single pulse amplitudes vary with?
[Ca2+]o, but PPF effect sizes vary even more
How does changing [Ca2+]o affect EPPs from single stimulus pulses (1 presynaptic AP)?
- [Ca2+]o affects amount of neurotransmitter release by the 4th power (release is proportional to [Ca2+]o4)
- this implies EPP amplitude can be directly determined by [Ca2+]i
How does varying [Ca2+]o affect the PP ratio in a synapse?
example:
- PPF increases in proportion to [Ca2+]o
- implies that [Ca2+]i perhaps reaches higher levels on the second pulse – hypothesis called the ‘residual calcium’ hypothesis
What is the residual calcium hypothesis?
Ca2+]i perhaps reaches higher levels on the second pulse
suggested by the fact that PPF increases in proportion to [Ca2+]o
How does the residual calcium hypothesis explain synaptic facilitation? What is Katz & Miledi’s hypothesis?
in terms of [Ca2+]i and vesicle release
Katz & Miledi’s Hypothesis: since EPSC amplitude can be predicted by [Ca2+]i then residual levels of calcium lingering in the active zone would contribute to the next pulse, if it occurs quickly enough after the first pulse
What must happen to any Ca2+ that enters a cell? Why?
How does this contribute to synaptic facilitation?
must be actively pumped (by ion transporters) either back out of the cell, or into intracellular stores, in order to return [Ca2+]i to its baseline level
- pumps take time, therefore if another pulse occurs quickly enough after the first, there may be a small fraction of residual calcium still present when VGCCs reopen
- total new level of calcium will represent the new influx of calcium + the residual component
For short interval PPF, what does Ca contribute to?
contributes directly to expression and induction
How is short-term synaptic depression related to calcium levels?
through neurotransmitter release
- in synapses that typically show PPD during normal conditions, amount of rapid depression can be reduced by lowering [Ca2+]
- this effect can also be seen in PP ratio experiments
What has been proposed to explain rapid short-term depression? How does it work?
RRP depletion
- if most or all vesicles in the RRP have been released by previous stimuli, now vesicles have to be mobilized from the recycling pool – a less efficient process that may not have completely filled the release sites at the active zone before the next stimulus arrives
- because of this, overall release probability (p, or likelihood of releasing vesicles for a single stimulus) from the synapse will be reduced for the next stimulus that arrives, and therefore the synaptic response will be depressed
How are synaptic vesicles organized?
into different physiological vesicle pools, which are more or less easy to be released (L10)
Mechanisms of Short-term Plasticity
Facilitation
explained by residual Ca2+
- induction: Ca2+
- expression: Ca2+
Mechanisms of Short-term Plasticity
Rapid Depression
explained by receptor desensitization (postsynaptic expression) or RRP depletion (presynaptic expression)
- induction: vesicle fusion / transmitter release
- expression: docking and priming / receptor inactivation
What determines whether any specific synapse would show PPF or PPD? (ie. rapid increases or decreases in synaptic strength?)
initial release probability (what proportion of RRP is released by the very first stimulus)
- if the synapse releases most of RRP on the first stimulus (starting off strong), it is a depressing synapse
- if the synapse only releases some of RPP on the first stimulus, it can still take advantage of RRP for the next stimulus
Does augmentation have some relation to Ca2+?
yes – it some relation to Ca2+ levels because changing [Ca2+]o affects whether or not you see augmentation
HOWEVER…
Why can’t augmentation be explained by the residual calcium hypothesis?
augmentation occurs over timescales that are longer than the duration that residual Ca2+ is present in the axon terminal after an AP
Ca2+ cannot be directly involved in expression over this time scale – need to start thinking about Ca2+ involved in induction
Which aspect of augmentation cannot be directly explained by Ca2+?
time frame is too long for residual calcium to worK – will get back to original level of calcium (1 second is more than enough time – pumps are slower than channels, but 1 second is enough time to pump everything back out and return to original calcium levels)
What can intracellular calcium act as to trigger synaptic enhancement?
second messenger
Role of Intracellular Calcium in Triggering Synaptic Enhancement
What can Ca2+ do when elevated for a sustained period?
can bind to:
- effector proteins – ie. Ca2+-sensitive ion channels, synaptotagmin
OR can indirectly activate various intracellular signal cascades (which leads to changes in synaptic properties) by binding to:
- regulator enzymes – ie. PKC
- transducer proteins which activate other kinases – ie. calmodulin
What proteins do signal transduction cascades affect?
proteins within the active zone/axon terminal and/or PSD
How does phosphorylation (and other signalling cascade-mediated changes) affect proteins?
affects the efficiency with which synaptic proteins carry out their roles
What is the effect of PKC phosphorylating SNAREs?
enhances vesicle docking and release
What is PKC enzyme activated by?
by Gαq signalling and/or [Ca2+]i increases
What does PKC phosphorylate?
many active zone proteins
How does PKC affect augmentation?
inhibiting overall PKC activity does not affect the response to the first stimulus, but reduces the response to a second, delayed stimulus (prevents augmentation)
What can cause synapses to undergo short-term depression?
sustained stimulation of most synapses at a moderate to high frequency (> ~20 Hz) usually leads to temporary synaptic depression lasting for a few minutes
How is the amount of short-term depression reduced?
amount of depression observed is reduced by reducing [Ca2+]o, and is proportional to the amount of transmitter released by prior ‘conditioning’ stimuli
more previous release → more subsequent depression
What are autoreceptors?
metabotropic receptors that respond to the neurotransmitter released by that axon terminal (L12)
Where are autoreceptors found?
expressed in presynaptic axon terminals
How do autoreceptors contribute to depression?
contribute to depression over intermediate time scales (seconds to minutes)
autoreceptors are typically of the Gi/o subtype, so what we previously discussed as ‘negative feedback’ on neurotransmitter release through alterations to VGCCs and VGKCs can actually be considered as a form of short-term depression over a medium time scale
Mechanisms of Short-term Plasticity
Residual Ca2+
facilitation
Mechanisms of Short-term Plasticity
Ca2+ mediated and/or Gαs and Gαq transduction cascades
- augmentation
- potentiation
Mechanisms of Short-term Plasticity
Receptor Desensitization + RRP Depletion
rapid depression
Mechanisms of Short-term Plasticity
Gαi-mediated Transduction Cascades
short to medium term depression
What is the basic theory of synaptic plasticity (Hebb’s postulates)?
particular patterns of activity between connected neurons changes the strength of the synaptic connections between them
Physiological processes of synaptic plasticity can be roughly divided into mechanisms of…
induction, expression, and maintenance
Mechanisms of short term enhancement and depression of synapses are predominantly…
- induced and expressed in presynaptic terminal
- mostly involve calcium: either directly through its effect on vesicle release, or indirectly via transduction cascades
