Ca in short-term plasticity

Adjunto:

• Short-term synaptic plasticity

1. depletion of the readily releasable pool (RRP)

   Nota:

   • After prolonged stimulation, depletion of the readily releasable pool can result from physical depletion of the total pool of synaptic vesicles observed in electron microscopy at neuromuscular and ganglionic synapses
   1. light-induced uncaging of Ca2+

      Nota:

      • At the calyx of Held, even after complete depletion of the readily releasable pool of vesicles by repetitive stimulation, substantial neurotransmitter release can be elicited by light-induced uncaging of Ca2+ simultaneously throughout the nerve terminal
      • Remarkably, the remaining synaptic vesicles respond as rapidly as those recruited by action potentials and have similar sensitivity to Ca2+
      1. vesicles- near or far from Ca Channels
   2. remaining vesicles

      Nota:

      • Thus, depletion of the readily releasable pool by repeated action potentials reflects selective depletion of docked vesicles near functionally active Ca2+ channels, leaving other distant docked vesicles ready to be released with normal sensitivity by the uncaging of Ca2+ near them
2. reduced Ca entry
   1. changes in action potential waveform
      1. Borst and Sakmann (1999)
   2. feedback inhibition by metabotropic autoreceptors

      Nota:

      • has a small contribution
      1. von Gersdorff et al (1997)
   3. inactivation of Ca2+ channels

      Nota:

      • Ca2+-dependent inactivation of the presynaptic P/Q-type current correlates with the rapid phase of synaptic depression
      1. CaM inhibitors

         Nota:

         • partially relieve inactivation of the presynaptic Ca2+ current and reduce synaptic depression
         1. Xu and Wu (2005)
      2. transfected SCG neuron synapses- role of CBD
         1. Mochida et al (2008)

            Nota:

            • Deletion of the CBD in the C terminus of transfected CaV2.1 channels, which blocks inactivation of P/Q-type Ca2+ currents, reduced paired-pulse depression and rapid synaptic depression during trains
            • >>  CaM binding to the CBD induces inactivation of presynaptic CaV2.1 channels, which in turn causes rapid synaptic depression evoked by physiological activity patterns
      3. auxiliary CaVβ subunits

         Nota:

         • Important in inactivation of Ca channels- Expression of CaVβ2a in cultured neurons favors synaptic depression, whereas expression of CaVβ4a favors facilitation
         1. Xie et al (2007)

Adjunto:

• Short-term synaptic plasticity

1. residual Ca2+

   Nota:

   • short-term facilitation is caused by residual Ca2+that builds up from action potentials
   1. effector mechanisms

      Nota:

      • proposed mechanisms
      1. 1. saturation of local Ca2+ buffers, such as calbindin-D28k and parvalbumin

         Nota:

         • These Ca2+ buffers are partially saturated by residual Ca2+, resulting in an additional Ca2+ increase during subsequent action potentials 
         1. Muller et al (2007)

            Nota:

            • studied the role of mobile endogenous presynaptic Ca2+buffer(s) in modulating paired-pulse facilitation at calyx of Held using presynaptic whole cell recordings 
            1. Whole-cell recordings

               Nota:

               • The fast [Ca2+]i decay was restored by adding the slow Ca2+ buffer EGTA (50–100 μM) or parvalbumin (100 μM), a Ca2+-binding protein
            2. parvalbumin knockouts

               Nota:

               • the decay of [Ca2+]i and facilitation was slowed approximately twofold compared with wild-type mice
      2. 2. residual Ca2+ binds to a Ca2+ sensor other than that for exocytosis and activates it to increase the probability of release

         Nota:

         • Unlike Ca2+ buffers, Ca2+ sensor proteins bind Ca2+ and undergo a conformational change to regulate targets
         • Activation of a Ca2+sensor protein could increase Ca2+ entry and thereby enhance neurotransmitter release according to the power law  or could directly modulate exocytosis
         1. Reviewed by Burgoyne and Weiss (2001)
         2. see Ca sensors
2. Ca2+ entry

   Nota:

   • Increased Ca2+ entry could result from Ca2+-dependent increase in Ca2+channel activity by facilitation, which occurs on the millisecond time scale. Alternatively, Ca2+ channel density at the active zone could be increased, which increases synaptic strength, but there is no evidence to date that Ca2+ channels can be inserted into active zones on the millisecond time scale.
   1. Inchauspe et al (2004; 2007)

      Nota:

      • Ca2+ entry through CaV2.1 channels is necessary for synaptic facilitation at the calyx of Held
      1. α1 subunit-deficient knock-out mice
         1. facilitation of presynaptic Ca2+ current and synaptic facilitation are lost
   2. account for only half of facilitation
      1. quantitative comparisons- Muller et al (2008)

1. CaM

   Nota:

   • calmodulin- CaM belongs to a superfamily of CaS (Ca2+ sensor) proteins
2. CaBP1

   Nota:

   • Ca2+-binding protein-1 It is co-localized with presynaptic CaV2.1 channels and binds to the CBD of the CaV2.1 α1 subunit
   1. increase inactivation, decrease facilitation

      Nota:

      • causes rapid CaV2.1 inactivation in a Ca2+-independent manner, and it does not support CaV2.1 facilitation
   2. Leal et al (2012)

      Nota:

      • CaBP1 and VILIP-2 to fine-tune short-term synaptic plasticity by regulation of CaV2.1 channels has been shown directly by expression of wild-type and mutant CaV2.1 channels with CaS proteins in SCG neurons
      1. IM motif and CBD mutations

         Nota:

         • lost functional effects These results show that CaBP1 and VILIP-2 act directly on CaV2.1 channels by binding to their C-terminal regulatory site and cause push-pull regulation of the form of short-term synaptic plasticity, with CaBP1 favoring depression and VILIP-2 favoring facilitation. 
      2. Co-expression

         Nota:

         • coexpression of VILIP-2 with CaV2.1 channels under the conditions of our paired-pulse experiments had no effect- overall null effect
      3. CaBP1
         1. Expression of CaV2.1 with CaBP1

            Nota:

            • Expression of CaV2.1 channels with CaBP1, which enhances inactivation of CaV2.1 currents, causes loss of synaptic facilitation and enhanced synaptic depression in SCG neurons
            • We expressed CaV2.1 channels and CaBP1 or VILIP-2 by injecting cDNA into an identified SCG neuron, and we recorded excitatory postsynaptic potentials (EPSPs) from a neighboring synaptically connected but untransfected neuron
            1. CaBP1 showed paired pulse depression

               Nota:

               • suggesting that it leads to synaptic depression
         2. CaBP1 + mutant CaV2.1-of CaS-binding sites
            1. Coexpression of CaBP1 does not further reduce facilitation of synapses expressing the mutant CaV2.1I
               1. facilitation of CaV2.1 channels by CaBP1 occures via CaS proteins interacting with the IM and CBD domains
      4. VILIP-2
         1. Expression of CaV2.1 with VILIP-2

            Nota:

            • Expression of CaV2.1 with VILIP-2, which enhances facilitation of CaV2.1 currents, causes reduced synaptic depression and enhanced synaptic facilitation
            1. synaptic facilitation similar to controls

               Nota:

               • synaptic facilitation followed by synaptic depression that was similar to that in control synapses So it doesn't enhance facilitation compared to controls
               1. Why?

                  Nota:

                  • possibly because differences in Ca2+ dynamics in presynaptic active zones versus nonneuronal cells
                  1. high level of basal synaptic facilitation may occlude effects of VILIP-2
            2. Contradict previous studies in transfected cells

               Nota:

               • VILIP-2 reduces inactivation of Ca2+ currents during trains of repetitive depolarizations and thereby enhances and prolongs Ca2+ current facilitation
               1. Lautermilch et al (2005)
                  1. decrease inactivation, increase facilitation
            3. So, raised external Ca2+ to enhance PoR and synaptic depression
               1. synapses expressing VILIP-2 show significantly more facilitation and significantly less depression
         2. VILIP-2 + CaV2.1I mutant of CaS-Binding Sites
            1. Coexpression of VILIP-2 has no effect on depression or facilitation

               Nota:

               • which means its dependent on CaS-binding sites
3. VILIP-2

   Nota:

   • Visinin-like protein-2 has complementary regulatory effects to CaBP1- opposite effect to CaBP1
   1. increase facilitation, decrease inactivation

      Nota:

      • it increases CaV2.1 facilitation but inhibits CaV2.1 inactivation
   2. VILIP-2 uses a complex set of interactions of three of its domains with the IM and CBD motifs in regulation of CaV2.1 channels
4. NCS-1

   Nota:

   • neuronal Ca2+ sensor-1 The evidence suggests that residual Ca2+ facilitates the activity of CaV2.1 channels via NCS-1.
   1. increases presynaptic facilitation at the calyx of Held by accelerating activation of P/Q-type Ca2+ currents
   2. expression of NCS-1 enhances synaptic transmission

Adjunto:

• Short-term synaptic plasticity

1. facilitation and inactivation relies of CaM

   Nota:

   • which binds to a modified IQ-like domain (IM motif) and a downstream CaM-binding domain (CBD) 
   • Ca2+ causes facilitation through interaction of the C-terminal lobe of CaM with the IM motif, whereas global Ca2+ causes inactivation of CaV2.1 channels by binding of the N-terminal lobe of CaM to the CBD
   • Ca2+ binding to CaM prebound to CaV2.1 channels may induce two sequential conformational changes, which in turn induce facilitation and inactivation
   1. Facilitation
      1. mutations

         Nota:

         • reduced by mutations in C-terminal EF-hands of CaM and by complementary mutations in the IM motif of CaV2.1 channels
         1. C-terminal and IM mortif
         2. Lee et al (1999; 2003)
   2. inactivation
      1. mutations

         Nota:

         • in the N-terminal lobe of CaM and by deletion of the CBD of CaV2.1 channels
         1. N-terminal and CBD

1. CaV

   Nota:

   • voltage-gated Ca channels
   1. presynaptic CaV2

      Nota:

      • a subfamily that regulates synaptic transmission
      1. binds Ca2+ sensor protein calmodulin (CaM)2

         Nota:

         • to a site in their C-terminal domain
         1. induces facilitation and inactivation of CaV2.1 channel

            Nota:

            • in response to repetitive stimuli
            • can cause facilitation and depression of synaptic transmission 
   2. CaV1
   3. subunits
      1. α1
         1. pore
         2. voltage sensors
         3. gating apparatus
      2. β

         Nota:

         • The intracellular β subunit is a hydrophilic protein
         1. channel function
         2. enhance cell-surface expression of α1
      3. γ

         Nota:

         • having four transmembrane segments is a component of skeletal muscle Ca2+ channels
      4. α2δ
         1. enhance cell-surface expression of α1 subunits
         2. important for Ca entry and exocytosis in active zones
2. Presynaptic Ca current
   1. initiates exocytosis
   2. release probability

      Nota:

      • The release probability of a single synaptic vesicle increases with the number of Ca2+channels at the active zone
   3. Vesicle fusion and exocytosis depends on -SNARE, SNAP-25, Munc18

      Nota:

      • A primed SNARE complex requires the Ca2+-binding protein synaptotagmin, which provides rapid Ca2+-dependent regulation of exocytosis
      • Binding of SNARE proteins to the synaptic protein interaction (termed synprint) site (Fig. 2A) regulates expression, localization, and function of CaV2 channels
3. Neurotransmitter release:
   1. synchronous (phasic)
      1. presynaptic Ca2+ current

         Nota:

         • Synchronous release driven by precisely timed presynaptic Ca2+ current results in fast postsynaptic responses
         1. Ca2+ sensor synaptotagmin
   2. asynchronous (tonic)
      1. residual Ca2

         Nota:

         • Slower asynchronous release results from residual Ca2+ remaining in the terminal after an action potential
         1. Ca2+ sensor Doc2
   3. low-probability spontaneous (miniature) release
      1. fluctuations in resting Ca2+

         Nota:

         • Spontaneous release results from fluctuations in resting Ca2+ concentrations or from Ca2+ release from internal stores