Short-term synaptic plasticity

Annotations:

Short-term synaptic plasticity- decays to baseline usually within 30-60 minutes

MECHANISMS
1. Synaptic facilitation
  1. Residual calcium
    Annotations:
    - one mechanism- residual calcium (Cares) that persists in the presynaptic terminal following synaptic activation
    - Ca(res) increases the probability of release by binding to a sensor distinct from synaptotagmin, the sensor for synchronous release, and activating a site distinct from the low affinity sites on synaptotagmin that are responsible for vesicle fusion [36 and 37]. At present no such calcium sensor has been identified.
    1. Felmy et al (2003)
      Annotations:
      - the intracellular Ca(2+) sensitivity of transmitter release at the calyx of Held is largely unchanged during facilitation, which leaves an increased microdomain Ca(2+) signal as a possible mechanism for facilitation. We measured the Ca(2+) dependencies of facilitation, as well as of transmitter release, to estimate the required increment in microdomain Ca(2+). These measurements show that linear summation of residual and microdomain Ca(2+) accounts for only 30% of the observed facilitation. However, a small degree of supralinearity in the summation of intracellular Ca(2+) signals, which might be caused by saturation of cytosolic Ca(2+) buffer(s), is sufficient to explain facilitation at this CNS synapse
  2. Saturation of endogenous calcium buffers
    Annotations:
    - Another potential mechanism for facilitation involves calcium-binding proteins within presynaptic terminals that normally intercept calcium ions between calcium channels and release sites, thus reducing the initial probability of release
    1. Blatow et al (2003)
      Annotations:
      - saturation of the endogenous fast Ca2+ buffer calbindin-D28k (CB) plays a major role in PPF at CB-containing synapses. Paired recordings from synaptically connected interneurons and pyramidal neurons in the mouse neocortex revealed that dialysis increased the amplitude of the first response and decreased PPF. Loading the presynaptic terminals with BAPTA or CB rescued the effect of the CB washout. We extended the study to the CB-positive facilitating excitatory mossy fiber-CA3 pyramidal cell synapse. The effects of different extracellular Ca2+ concentrations and of EGTA indicated that PPF in CB-containing terminals depended on Ca2+ influx rather than on the initial release probability. Experiments in CB knockout mice confirmed that buffer saturation is a novel basic presynaptic mechanism for activity-dependent control of synaptic gain.
  3. calcium currents
    Annotations:
    - calcium currents can be enhanced in a use-dependent manner
    1. Catterall and Few (2008)
      Annotations:
      - calcium-sensitive proteins such as calmodulin have previously been implicated in use-dependent increases in presynaptic calcium entry
    2. Mochida et al (2008)
      Annotations:
      - A crucial link among these two sets of observations and facilitation was made when it was found that mutating P-type calcium channels to prevent calcium-dependent facilitation of calcium currents also suppressed synaptic facilitation
2. Activity-dependent synaptic depression
  1. vesicle depletion
    1. 5% of vesicles released
      Annotations:
      - There are typically hundreds of vesicles associated with one active zone, but usually fewer than 5% of these vesicles are readily released with repeated stimulation
      - The number of vesicles released by an action potential depends on the size of this readily releasable pool (RRP) of vesicles, and on the probability of release of these vesicles
      1. RRP
        Annotations:
        readily releasable pool
      2. Pr
        Annotations:
        Probability of release
    2. high initial PoR>> increased depression
      Annotations:
      - Because the number of vesicles in the RRP is limiting, if an action potential releases a large fraction of the RRP, subsequent stimuli delivered before RRP replenishment will release fewer vesicles [1]. This model predicts that depression will increase when the initial release probability and the frequency of activation are increased
      1. corticothalamic synapses
        Annotations:
        this occurs in
      2. Auditory brainstem synapses
        Annotations:
        this occurs in
    3. Recovery
      Annotations:
      - Recovery can be significantly accelerated by elevations of presynaptic calcium in a calmodulin-dependent manner
      1. increase presynaptic Ca
    4. where transmitter release is artificially reduced, as when extracellular calcium concentration is lowered, depression is attenuated
  2. inactivation of release sites
    1. Fusion
      Annotations:
      - fusion of a vesicle at a release site can inhibit subsequent fusion events at that site even if the RRP is not depleted
    2. vesicular membrane proteins
      Annotations:
      - This proposed site inactivation lasts for seconds following exocytosis and could reflect the time it takes to clear vesicular membrane proteins, which get incorporated into the plasma membrane upon vesicle fusion, from the release site
    3. Recovery by endocytosis
      1. Hosoi et al (2009)
        Annotations:
        Blocking endocytosis presynaptically reduces the recruitment of readily releasable vesicles and leads to more pronounced depression during trains
        These findings are consistent with endocytosis clearing vesicular membrane proteins from the plasma membrane where they interfere with release, thereby allowing sites to recover from inactivation more rapidly than if these proteins were removed by diffusion within the membrane.
  3. decreased presynaptic calcium influx
    1. auditory brainstem
      Annotations:
      - At the calyx of Held, a synapse in the auditory brainstem, calcium-dependent decreases in calcium influx contribute to synaptic depression
      1. Xu and Wu (2005)
        Annotations:
        decreased release probability is caused by a calcium-induced inhibition of presynaptic calcium channels, particularly P/Q-type channels at the calyx of Held in rat brainstem. This mechanism was the dominant cause of STD in a wide range of stimulation conditions, such as during 2 to 20 action potential-equivalent stimuli (AP-e) at 0.2-30 Hz and after 2 to 20 AP-e at 0.2-100 Hz. Only during > or = 100 Hz AP-e was depletion the dominant mechanism
    2. Modulation by Ca sensing proteins (CaS)
      Annotations:
      - Calcium-sensing proteins (CaS), including calmodulin, calcium binding protein 1 (CaBP1), and neuronal calcium sensor 1 (NCS-1), interact with calcium channels and bidirectionally modulate their function
    3. Mochida et al (2008)
      Annotations:
      - recent study in cultures of superior cervical ganglion neurons provides compelling evidence that calcium-dependent inactivation of calcium channels can contribute to synaptic depression: Deleting the calmodulin-binding domain on P-type calcium channels to prevent their inactivation reduces synaptic depression
  4. Proteins
    Annotations:
    - Pharmacological or genetic manipulation of many proteins can influence depression
    1. RIM proteins
      Annotations:
      - The multidomain proteins RIM1 and RIM2 are integral components of the cytomatrix at the active zone, interacting with most other active zone-enriched proteins as well as synaptic vesicle proteins
      1. Calakos et al (2004)
        Annotations:
        dramatic alleviation of depression when RIM proteins are eliminated caused by decreased release probablitiy
    2. Bassoon
      Annotations:
      - a protein of the active zone
      1. Hallermann et al (2010)
        Annotations:
        For example, at the cerebellar mossy fiber-to-granule cell synapse genetic deletion of Bassoon, a protein of the active zone, results in more pronounced synaptic depression. Additional results suggest that Bassoon reduces synaptic depression by aiding vesicle replenishment at release sites
        Knockout mice
  5. receptor desensitization
  6. GLIAL
    Attachments:
    - Modulation of LTP
3. Receptor mediated
  Attachments:
  - Receptor mediated STP
  1. Gi/o-coupled receptors
    1. GABA
    2. CB1
      1. DSI/ DSE
    3. Heteroreceptors
  2. ionotropic receptors
    1. Kainate receptors
4. Augmentation (7s) and post-tetanic potentiation (PTP, 2-3s)
  Annotations:
  - PTP lasts for tens of seconds to minutes, and becomes longer lasting when the stimulus frequency and duration are increased. Augmentation is induced with less prolonged stimulation and lasts for 5–10 s, PTP lasts for 2-3s
  1. PTP
    Annotations:
    - PTP is accompanied by a decrease in paired-pulse plasticity, suggesting an increase in the probability of release
    - This increase may result from either an increase in presynaptic calcium entry or changes in the release machinery itself
    1. Presynaptic
      Annotations:
      - evidence for it being a presynaptic mechanism
      1. Korogod et al (2007)
        Annotations:
        At the calyx of Held synapsetetanus-induced increases in action potential-evoked calcium entry could contribute to PTP
        increase in Ca entry
      2. Mochida et al (2008)
        Annotations:
        but at superior cervical ganglion cell synapses calcium-induced enhancement of calcium channels does not contribute significantly to PTP even though it accounts for approximately half of augmentation
        weak contribution of enhancement of Ca channels
      3. tetanic stimulation elevates Ca(res)
        Korogod et al (2007)
        Annotations:
        At the calyceal synapse, tetanic stimulation elevates Cares to several hundred nanomolar, and this Cares decays with a time course similar to PTP [44 and 50], suggesting that the time course of Caresmay dictate the time course of PTP
        Brager et al (2003)
        Annotations:
        At the hippocampal synapses, Cares decays more rapidly than PTP [45 and 51], suggesting that Cares activates biochemical cascades with slower kinetics that regulate the duration of PTP
      4. vesicle pool size
        increase in vesicle pool
        Annotations:
        Tetanic stimulation can increase the size of the vesicle pool that is released by a high-frequency train (RRPtrain, Figure 2a) [48], but paradoxically there is little change in the overall size of the RRP determined by large prolonged presynaptic voltage steps
        differences in the RRPtrain and RRP
        Annotations:
        differences in the RRPtrain and RRP can be explained by non-uniformity in the vesicles that make up the RRP [62 and 63]. Vesicles that are readily released by action potentials are thought to be near voltage-gated calcium channels, whereas it is difficult for action potentials to liberate vesicles that are far from voltage-gated calcium channels [12•]. In contrast, vesicles both near and far from voltage-gated calcium channels contribute to the RRP that is determined using protocols that lead to large and prolonged calcium increases [62 and 64]. Such non-uniformity in vesicles complicates the interpretation of short-term plasticity. For example, an increase in the calcium sensitivity of vesicles might increase RRPtrain by making some distant vesicles responsive to action potentials.
      5. Wu and Saggau, 1994; Tang and Zucker, 1997
        Annotations:
        The concentration of Ca2 in terminal boutons rises during PTP, suggesting that, like facilitation, it is a presynaptic process
        increase in presynaptic Ca
    2. mechanisms that lead to
      1. Pr altered independently
        Annotations:
        The probability of release can also be altered independently of changes in presynaptic calcium entry. For example, protein kinase C (PKC), which has been implicated in PTP [44, 45 and 46], can decrease the calcium cooperativity such that the same calcium signal can evoke the release of more synaptic vesicles
      2. Tetanus-induced alterations
        Annotations:
        Tetanus-induced alterations in the properties of the RRP can also contribute to PTP
        Lee et al (2008)
        Annotations:
        At the calyx of Held synapse, it is thought that activation of myosin light chain kinase (MLCK) can produce alterations in the RRP that can account for about 20% of PTP
        MLCK
        He et al (2009)
        Annotations:
        At the calyx of Held synapse, tetanic stimulation can cause some of the vesicles to fuse with each other before fusion with the plasma membrane, and thereby increase the size of miniature synaptic currents
      3. calcium-sensitive proteins to PTP
        Annotations:
        There is still considerable uncertainty about the relative contributions of PKC, Munc13, and other calcium-sensitive proteins to PTP, and it has even been suggested that related forms of synaptic enhancement require both Munc13 and PKC, as well as its downstream target Munc18
        Munc13
        Shin et al (2010)
        Annotations:
        Munc13 proteins, which are required for synaptic transmission, are essential for vesicle priming and can regulate short-term synaptic plasticity
        PKC
        Annotations:
        Pharmacological studies support a role for PKC [44, 45, 55 and 56], but these studies have been called into question [48] and molecular genetic evidence is unavailable, in part because there are many PKC isoforms [57].
  2. weak high-frequency stimulation
    Annotations:
    - At perforant path synapses, a weak high-frequency train leads to a substantial elevation of test responses immediately after the train, which declines back to baseline within a few minutes
  3. (-) long stimulus trains
    Annotations:
    - With longer stimulus trains, PTP is superimposed on a background of LTP, and this complicates the analysis of the time course of both phenomena.
    1. Controls- McNaughton, 1982
      Annotations:
      - When suitable controls are conducted, PTP is seen to be the sum of two exponential processes known as augmentation and potentiation that in the medial perforant path have time constants of 7 s and 2 to 3 minutes, respectively
5. ROLE of CALCIUM
  Attachments:
  - Ca in short-term plasticity
Paired pulse stimulation
Annotations:
- The aftereffects on synaptic transmission of a single stimulus can be tested by delivering a second stimulus at a variable time after the first.
1. PF- DG
  Annotations:
  - When pairs of stimuli are delivered to the perforant path, the amplitude of the second response recorded in the molecular layer of the dentate gyrus in vivo is typically facilitated at interstimulus intervals of less than 200 to 300 ms and depressed at longer intervals of up to a few seconds (McNaughton, 1980
2. SC- CA1
  Annotations:
  - Similar effects are seen at Schaffer-commissural synapses in area CA1 (Andersen, 1960)
3. Magleby, 1979
  Annotations:
  - Paired-pulse facilitation and depression were first studied in the neuromuscular junction and appear to be a common feature of all chemically transmitting synapses
  1. PPF
    Annotations:
    - It reflects the fact that at many synapses, such as those made by Schaffer commissural axons, an invading action potential has a greater chance of evoking exocytosis of neurotransmitter when it arrives within a few tens of milliseconds of a preceding action potential.
    1. facilitation is inversely related to the initial probability of release
      1. increase in PPR= reduction in Pr; reduction in PPR= increase in Pr
        only changes in PPR implicate presynaptic mechanisms
    2. potentiation
  2. PPD
    1. depotentiation
4. Test for pre vs postsynaptic
  1. McNaughton (1982)
    Annotations:
    - based on the fact that the higher the probability of release, the less scope there is for presynaptically mediated facilitation, and so the smaller is the observed degree of paired-pulse facilitation
  2. suggestive but not conclusive
    Annotations:
    - could be other postsynaptic mechanisms
    1. LTP example
      Annotations:
      - For example, no change in facilitation would be observed if LTP resulted from recruitment of a population of silent boutons (that is, boutons with zero probability of release before the induction of LTP) that, following induction, assumed a distribution of release probabilities similar to that of the population activated before induction >> in this case it's still a presynaptic mechanism that recruited vesicles
      1. unsilencing of silent synapses
      2. more neurotransmitter in vesicles
    2. LTD example
      Annotations:
      - suppose PPF increases after the induction of LTD. The conventional interpretation would be that this reflects a reduction in Pr. However, there are plausible postsynaptic changes that could give rise to an increase in PPF. Thus, if LTD involves the internalization of receptors, and the probability of internalization is dependent on the binding of transmitter, receptors at those synapses with the highest Pr would be internalized first. In this model, the mean Pr of the remaining active synapses would steadily fall, and PPF would increase as a result of a purely postsynaptic change. Evidence for this model is found in mGluR-dependent LTD
    3. presynaptic change without change in PPF
      Annotations:
      - e.g., if LTP were achieved by unsilencing of a population of new release sites with a similar distribution of Pr to existing sites
  3. Other tests
    Annotations:
    - tests that check whether it's a postsynaptic mechanism?
5. Probability of release (Pr)
  Annotations:
  - Facilitation is a function of the mean Pr of the synapses under study. Clearly if Pr is at or close to 1, there is little or no scope for facilitation
6. McNaughton (1982)
  1. increase in Pr, decrease in facilitation
7. Quantal analysis
  Annotations:
  - When the quantal variable n, the number of release sites, is large (e.g., when stimulating many Schaffer-commissural fibers) the stochastic nature of neurotransmitter release is seen as trialby- trial fluctuations in the amplitude of the evoked synaptic response That is neurotransmitter release varies in each stimulation (Pr<1)
  1. coefficient of variance (CV =SD/mean)
    Annotations:
    - sensitive to changes in Pr and n but also, in some circumstances, to postsynaptic factors
    1. if Pr= 1, CV decreased
      Annotations:
      - because there is little variability in the release of neurotransmitter
    2. decrease in failures= increase Pr
    3. n>1, increased CV
      Annotations:
      - When multiple sites are activated (n >1) there is an additional variance due to the between-site variation in quantal size. This inter-site variability could be large, reflecting, for example, differences in receptor number and electrotonic distance from the recording site
    4. changes in CV indicates a presynaptic mechanism
      1. decreased CV= increased Pr
  2. quantal amplitude (q)
    Annotations:
    - size of postsynaptic response in response to neurotrasmitter release The magnitude of this response varies from trial to trial as a result of the stochastic nature of postsynaptic channel opening and fluctuations in the amount of L-glutamate released
  3. n= no. of release sites
  4. relative contributions of n, Pr, and q= quantal analsis
    Annotations:
    - The study of the relative contributions of n, Pr, and q to changes in synaptic efficacy is the subject of quantal analysis
    - Typically, quantal analysis involves collecting many responses to plot an amplitude frequency histogram. The mean amplitude of an evoked synaptic response is simply n.Pr.q. The spacing between peaks in the histogram provides an estimate of q. A change in q alters the interpeak spacing without altering the amplitudes of the peaks, whereas a change in n or Pr modifies the amplitudes of the peaks but not the spacing between them
  5. (-) difficulty of making accurate measurements
    Annotations:
    - Accuracy requires high quality voltage-clamp recordings, so events are measured (as far as possible) at the same membrane voltage. It also requires the elimination of as many confounding variables (e.g., voltage-dependent conductances that may be imperfectly clamped, and synaptic inhibition) as is practical
  6. (-) unitary EPSCs in hippocampal neurons are very small
    Annotations:
    - As a result, it is difficult to distinguish all of the EPSCs above the background noise. Consequently, estimates of the frequency and amplitude distributions of miniature EPSCs can be inaccurate, and small evoked EPSCs may be misclassified as failures.
    1. (+) dendritic recordings
      Annotations:
      - The technically demanding technique of dendritic recording close to the site of synaptic activation improves the signal-to-noise ratio; using this approach it has been shown that EPSCs at Schaffer commissural synapses can be generated by fewer than five AMPA receptors
  7. (-) quantal variance (both inter- and intra-site) is often large
    Annotations:
    - making it difficult to construct clean histograms for quantal analysis.
  8. (-) interpertations
    1. n or Pr= presynaptic; q= postsynaptic
      Annotations:
      - however, these parameters could be interpreted in different ways a decrease in failures may be due to the unsilencing of silent synapses (post-synaptic) For example, anincrease in q could be due to more neurotransmitter contained in a synaptic vesicle. In hippocampalneurons, LTP is often associated with a decrease in the failure rate
8. protocol
  Annotations:
  - two stimuli are delivered (in the presynaptic neuron) with an interval of, e.g. 50 ms, and the amplitude of the first and second synaptic responses are compared (responses are recorded in the postsynaptic neuron). The amplitude of the second response relative to the first (facilitation ratio) is then a reflection of the increase in the probability of transmitter release (Pr).
Characteristic
1. transient form of LTP (TLTP)
  1. Volianskis and Jensen, 2003
    1. decays in an activity dependent manor
      Annotations:
      - If afferent stimulation is discontinued after tetenization, STP appears at full strength and decays with the same time course when afferent stimulation is resumed, even when the intervening period is as long as 6 hours
2. frequency and magnitude
  Annotations:
  - magnitude of STP was influenced by the frequency of afferent stimulation, such that higher frequencies favored larger STP
  1. explains variability
    Annotations:
    - In particular, a brief high-frequency tetanus followed by a low rate of test stimulation (as typically used in field potential recordings) would favor the generation of a large-magnitude STP with slow decay, whereas an intermediate frequency of stimulation for both the induction and expression periods (as typically used during pairing experiments) militates against STP. This may explain why pairing induced potentiation generally lacks the STP component.
    1. pairing protocol- lacks STP
    2. HFS- large STP
    3. low freq- small STP

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Short-term synaptic plasticity

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	Created by Cher Bachar almost 11 years ago