Receptor mediated STP

Nota:

• Bowery proposed the existence of two subtypes based on experiments showing the effects of baclofen, picrotoxin and bicuculline

1. GABA(B)

   Nota:

   • GABAB receptor for which baclofen was a selective agonist 
   1. K+ channels
      1. 1. Newberry and Nicoll (1985)
         1. baclofen hyperpolarised hippocampal pyramidal cells- chloride independent

            Nota:

            • This action was clearly not due to an increase in chloride conductance because in neurons loaded with chloride the baclofen response was still hyperpolarizing, despite the fact that GABA responses were depolarizing
         2. GABAB selective agonist

            Nota:

            • could activate a potassium conductance
         3. Can GABA increase K+ conductance?
            1. GABA(A) anta

               Nota:

               • in the presence of high concentrations of GABAA antagonists we were able to detect a hyperpolarization induced by GABA that was due to an increase in potassium conductance
      2. What is the nature of the potassium conductance activated by GABAB receptors?

         Nota:

         •  conductance has a delayed onset of 20 ms and lasts for many hundreds of ms.  >> could be indirect coupling because of the delay- similar to cardiac muscarinic K+ channels
         1. GIRK2 + K+ channels
         2. delayed onset
         3. indirect coupling?

            Nota:

            • These findings strongly suggested that GABAB receptors, as well as 5-HT1A receptors, activate a G-protein of either the Gi or Go type, which in turn activates potassium channels. These potassium channels are referred to as G-protein-coupled potassium channels or GIRKs
            1. 5-HT receptors
               1. Andrade and Nicoll (1987)

                  Nota:

                  • intracellular recording in in vitro brain slices-  Hippocampal pyramidal cells also respond to serotonin acting on 5-HT1A receptors generating a potassium conductance identical to that generated by GABAB receptor activation
               2. same pool of K+ for both receptors?
            2. Andrade et al (1986)
               1. same pool of K+ for both receptors?

                  Nota:

                  • Furthermore, fully activating the conductance with one agonist entirely occludes the action of the other, suggesting that the two receptors act on the same limited pool of potassium channels 
               2. G-protein coupled?

                  Nota:

                  • Evidence that G-proteins provided the link between the receptor and potassium channels was found by applying GDPβS, which blocks G-protein function, and by applying GTPγS, which locks G-proteins into an activated state.  >>GDPβS blocked the action of baclofen and serotonin and GTPγS generated a potassium conductance that occluded the action of the two agonists.
               3. Gi/o type

                  Nota:

                  • the actions of baclofen and serotonin were blocked by pertussis toxin, which selectively inactivates G-proteins of the Gi/o type
            3. GIRK2 knockouts

               Nota:

               • The GIRK2 knockout mouse was an extremely valuable tool because claims had been presented that GABA and the slow IPSP transmitter activated a different potassium conductance from baclofen [16], [17] and [18], challenging our proposal that these two agonists acted on the same receptor [9] and [19] and that baclofen and serotonin activated potassium channels with different single channel conductances [20], challenging our proposal that these two receptors shared the same conductance mechanism [13].
               1. (GIRK) G protein-coupled inwardly rectifying K+
               2. Luscher et al (1997)

                  Nota:

                  • transgenic mice lacking the GIRK2 gene The outward currents evoked by agonists for GABAB receptors, 5HT1A receptors, and adenosine A1 receptors were essentially absent in mutant mice, while the inward current evoked by muscarinic receptor activation was unaltered. In contrast, the presynaptic inhibitory action of a number of presynaptic receptors on excitatory and inhibitory terminals was unaltered in mutant mice. These included GABAB, adenosine, muscarinic, metabotropic glutamate, and NPY receptors on excitatory synapses and GABAB and opioid receptors on inhibitory synapses. These findings suggest that a number of G protein-coupled receptors activate the same class of postsynaptic K+ channel, which contains GIRK2.
                  • presynaptic inhibitory action of baclofen was unaltered in these mice, indicating that GIRK2 containing channels are not involved in the presynaptic action
                  1. 5-HT and GABA(B) coupled to similar GIRK2 channels
                  2. GIRK2 involved in post but not presynaptic action
               3. Jarolimek et al (1998)

                  Nota:

                  • A loss of postsynaptic currents has been reported for the weaver mouse, which has a pore mutation in the GIRK2 subunit
                  1. GIRK2 involved in post but not presynaptic action
   2. GIRK2 + K+ channels
   3. IPSP in hippocampus

      Nota:

      • Stimulation of afferents to CA1 hippocampal pyramidal cells results in a stereotyped series of potentials. These include: (1) an excitatory post-synaptic potential (EPSP), which if large enough, generates a single action potential; (2) a subsequent hyperpolarizing postsynaptic potential (IPSP), which peaks at a latency of about 50 ms; and (3) a late hyperpolarizing potential, which peaks at about 150 ms
      1. indirect link

         Nota:

         • A rigorous comparison of thebicuculline (GABA A anta) resistant action of GABA to that of the slow IPSP strongly implicated GABAB receptors as the mechanism for the slow IPSP
      2. direct link
         1. GABA(B) anta Phaclofen

            Nota:

            • antagonize the action of baclofen and more importantly the bicuculline resistant action of GABA BUT  had no effect on the action of serotonin, which activates the same potassium conductance Selective GABA antagonist
         2. Dutar and Nicoll (1988)
            1. phaclofen effectively blocked the slow IPSP
            2. (-) phaclofen is a weak antagonist

               Nota:

               • However, phaclofen is a weak antagonist and our results suggesting that GABAB receptors mediate the slow IPSP were challenged
         3. Solis and Nicoll (1992)
            1. Experiment was repeated with a potent GABA(B) anta

               Nota:

               • the slow IPSP is mediated by GABA released from interneurons and acting on GABAB receptors
   4. PRESYNAPTIC- short-term plasticity
      1. Decrease transmitter release
         1. Pierau and Zimmermann (1973)
            1. Baclofen

               Nota:

               • Inhibition of transmitter release was the first CNS action described for baclofen
         2. Luscher et al (1997)
            1. GIRK2 knockouts

               Nota:

               • In the hippocampus, the inhibition remains intact in the GIRK2 knockout mouse, indicating that a mechanism distinct from the postsynaptic action in involved
         3. Reduction in Ca channel function

            Nota:

            • accounts for the reduction in transmitter release
         4. Davies et al (1990)
            1. Paired pulse depression reversed by GABAB receptor antagonists

               Nota:

               • Paired pulse stimulation of inhibitory synapses at intervals of a few100 ms results in a depression of the second response. This paired pulse depression is partially reversed by GABAB receptor antagonists, indicating that synaptically released GABA can feed back onto presynaptic GABABautoreceptors and inhibit GABA release
         5. Lambert and Wilson (1994)
            1. depends of strength of stimulation

               Nota:

               • Interestingly, the involvement of GABAB receptors in paired pulse depression depends on the strength of stimulation [37]. Only when a substantial number of inhibitory synapses are activated are the presynaptic GABAB receptors recruited. This requirement, which is very similar to that for activation of postsynaptic GABAB receptors, indicates that pooling of GABA is necessary to reach high enough levels of GABA to activate the presynaptic GABAB receptors.
      2. Coopertaivity is needed to activate

         Nota:

         • under physiological conditions GABAB receptors would only be recruited during synchronous activity in inhibitory interneurons, as occurs, for instance, during the theta rhythm. In support of this hypothesis, it has been found that GABABreceptors are engaged during rhythmic activity in the hippocampus and sculpt this activity
         1. Scanziani (2000)
      3. Heterosynaptic inhibition

         Nota:

         • activity at one fibre can modulate/ modify the activity of a different fibre
         1. Isaacson et al (1993)

            Nota:

            • Repetitive, but not single, stimulation of inhibitory synapses resulted in a slow presynaptic inhibition of excitatory synaptic transmission that was blocked by GABAB receptor antagonists (Fig. 8). Application of a GABA uptake blocker greatly enhanced this heterosynaptic inhibition. These findings indicate that with repetitive activation of inhibitory synapses GABA can escape from the synapses and act at a distance from where it is released 
         2. GABA acts at a distance
      4. L-type Ca2+ channel-mediated short-term plasticity of GABAergic synapses
         1. Jensen and Mody (2001)

            Nota:

            • In dual recordings from hippocampal basket cells and granule cells, we now report that short-term plasticity of GABA release is controlled by L-type Ca2+ channels at presynaptic firing rates in the gamma-frequency (40 Hz) range4; at these GABAergic synapses, L-type Ca2+ channel antagonists converted post-tetanic potentiation into depression, identifying L-type Ca2+ channels as important modulators of plasticity at GABAergic synapses.
2. GABA(A)

   Nota:

   • GABAA receptor that increased chloride permeability and was blocked by picrotoxin and bicuculline

Nota:

• retrograde messengers- invovled in DSI and DSE which are presynaptic mechanisms of plasticity
• act on afferent GABAergic and glutamatergic transmission thereby leading to DSI and DSE

1. DSI and DSE

   Nota:

   • depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE)
   • related forms of short-term plasticity which relay of similar mechanisms of the same transmitter
   1. Endocannabinoids - retrograde messengers
      1. presynaptic type 1 cannabinoid receptors

         Nota:

         • reduce synaptic efficacy
         1. Wilson & Nicoll, 2001
            1. CB1R antagonist AM251

               Nota:

               • Whole cell recordings following the application of CB1R antagonist to CA1 pyramidal cells the EPSCs increase in amplitude- that is the DSI is inhibited
            2. DSI is mimicked and occluded by blocking uptake of endogenous CB1 ligands
            3. DSI and a CB1 agonist suppress IPSCs by the same mechanism
            4. The retrograde signal in DSI can disinhibit nearby neurons

               Nota:

               • The functional relevance of DSI
         2. Wilson et al (2001)
            1. CB1R knockouts

               Nota:

               • hippocampal DSI was soon shown to be absent in CB1R-deficient mice 
         3. Kreitzer and Regehr (2001a)
            1. DSE in Purkinje cells

               Nota:

               • DSE is mediated by the release of endocannabinoids and the consequent activation of presynaptic CB1Rs.
   2. induction
      1. Relies on retrograde signalling
      2. triggered by postsynaptic depolarization
      3. Calcium as a signal for induction
         1. blockers of calcium entry block DSI
            1. Llano et al., 1991; Lenz et al., 1998
         2. postsynaptic application of calcium chelating agents like EGTA and/or BAPTA prevent DSI/DSE
            1. Pitler & Alger, 1992; Glitsch et al., 2000; Kreitzer & Regehr, 2001a; Ohno-Shosaku et al., 2002a

               Nota:

               • Glitsch et al-  whole-cell patch-clamp recordings in rat cerebellar Purkinje cells- measuring Ca intracellular concs In response to chelating agents DSI was significantly reduced
         3. postsynaptic calcium uncaging is able to decrease frequency and amplitude of IPSCs

            Nota:

            • which is related to DSI
            1. Wang & Zucker, 2000

               Nota:

               • Whole cell patch clamp recording, Ca2+ measurement with ratiometric fluorescent dyes and photolysis of caged Ca2+ were combined to investigate the depolarization- and photolysis-induced suppression of inhibition (DSI and PSI) in rat hippocampal CA1 pyramidal cells
               1. photolysis of NPE depresses frequency of IPSCs while increasing intra Ca

                  Nota:

                  • A 5-s depolarization from −70 mV to 0 mV or a 6-s photolysis of nitrophenyl-EGTA (NPE) in cell bodies could each depress the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) and the amplitude of evoked IPSCs while elevating intracellular Ca2+ concentration ([Ca2+]i).
               2. DSI and PSI were linearly related to [Ca2+]i
               3. [Ca2+]i recovered more quickly than DSI, indicating that the duration of DSI is not set simply by the duration of [Ca2+]i elevation

                  Nota:

                  • but rather entails other rate-limiting processes
               4. Photolysis

                  Nota:

                  • Nitrophenyl-EGTA and DM-nitrophen are Ca2+ cages that release Ca2+ when cleaved upon illumination with near-ultraviolet light (laser photolysis)
                  • Caged compounds are unreactive compounds which are changed into active compounds by a reaction e.g. photolysis
      4. activating postsynaptic receptors linked to G proteins

         Nota:

         • induces a postsynaptic production of endocannabinoids and to inhibit afferent synaptic transmission
         1. Is NOT DSI/DSE

            Nota:

            • since they are not triggered by depolarization and since, in contrast to DSI/DSE, they do not seem to depend on postsynaptic calcium elevation
   3. First reports
      1. DSI
         1. Vincent et al.,1992

            Nota:

            • DSI was shown in stellate/basket cell inputs onto cerebellar Purkinje cells
         2. Pitler & Alger, 1992

            Nota:

            • GABAergic inputs onto CA1 pyramidal cells Exp- sIPSPs in current clamp and sIPSCs in voltage clamp are inhibited by a brief train of action potentials
      2. DSE
         1. Kreitzer & Regehr, 2001a

            Nota:

            • DSE was found at parallel and climbing fiber inputs of Purkinje cells
         2. Ohno-Shosaku et al., 2002b

            Nota:

            • and at glutamatergic inputs onto CA1 pyramidal cells
   4. Presynaptic nature

      Nota:

      • The presynaptic nature of the inhibitory effect on the afferent synaptic transmission, which defines DSI/DSE, was rapidly established, on the basis of the following observations: 
      1. (1) The postsynaptic sensitivity to GABA isn't modified during DSI
         1. Llano et al., 1991
      2. (2) The frequency, but not the amplitude of miniature inhibitory postsynaptic currents (mIPSCs) decreases during cerebellar DSI
         1. Llano et al., 1991
      3. (3) During DSI, the percentage of synaptic failures increases and PPR increases
         1. Alger et al., 1996
   5. Expression mechanisms
      1. powerful depression of synaptic transmission

         Nota:

         • inhibition of the output
      2. decreased miniature EPSCs

         Nota:

         • This suggests an action on basic release pathways unrelated to calcium entry, given that the frequency of miniature synaptic currents is usually considered independent from calcium entry.
      3. Potassium currents can be upregulated

         Nota:

         • This can lead to a shortening of the action potential duration (with a consequent reduction in the amount of calcium influx per spike), as well as to an increased threshold for action potential generation.
      4. N- and P/Q-type Ca voltage-dependence conductances can be inhibited

         Nota:

         • In presynaptic terminals, such effects would lead to a reduced calcium entry per action potential, and hence to reduced transmitter release.
   6. Role
      1. Neuroprotective role for DSE

         Nota:

         • We suggest that this neuroprotective role could come from DSE by the following mechanism: intracellular calcium increases in response to excitatory ionotropic receptor activation can trigger excitotoxicity and neuronal death following, for example, ischemic brain injury; the accumulation of intracellular calcium during such noxious events could lead to cannabinoid production, to CB1R activation and, finally, to a DSE-like presynaptic inhibition of glutamatergic transmission with neuroprotective effects.
         1. Diana and Marty (2004)
      2. DSI role in cerebellum
         1. control of output

            Nota:

            • CB1Rs are very strongly expressed in Purkinje cell pinceaux (Tsuo et al., 1998). This suggests that the possibility by CB1Rs of sensing Purkinje cell firing at this strategic location could influence the inhibitory input from presynaptic basket cells, thus controlling the output of the cerebellar cortex. 
            • On a larger scale, GABAergic interneurons can dictate the synchronized activity of large groups of neurons in cortical areas, thus generating specific network rhythms thought to be important in cognitive processes (Traub et al., 1999). This general pattern may apply to the synchronized activity of Purkinje cells (Isope et al., 2002). The inhibition of presynaptic firing occurring during DSI tends to simultaneously remove the GABAergic synaptic potentials from groups of neighboring Purkinje cells. This could transiently dissociate the time of firing of these Purkinje cells from the coordinated rythms of larger areas of the cerebellar cortex, with likely important consequences on the cerebellar output.

1. localized in mossy fibre axons
2. enhances transmitter release in an activity-dependent manner
3. Kamiya et al (2002)
   1. fluorescence recordings of presynaptic Ca2+ and voltage in hippocampal slices, paired-pulse stimul
   2. facilitation of Ca2+ influx into the MF terminals

      Nota:

      • not schaffer collaterals
      1. NOT Ca(res)
   3. KAR anta
      1. reduced PPR
   4. action potentials of MF axons are followed by prominent afterdepolarization, which is partly mediated by activation of KARs

      Nota:

      • the time course of the afterdepolarization approximates to that of the paired-pulse facilitation of Ca2+influx, suggesting that these two processes are closely related to each other
      1. amplifying presynaptic Ca2+ influx

         Nota:

         • may underlie the robust short-term synaptic plasticity at the MF–CA3 synapse in the hippocampus, and this process is mediated by KARs whose activation evokes prominent afterdepolarization of MF axons and thereby enhances action potential-driven Ca2+influx into the presynaptic terminals.
         1. How?
            1. inactivate K+ channels

               Nota:

               • depolarization of MF axons (Geiger and Jonas, 2000) may inactivate K+ channels shaping repolarization of presynaptic action potentials, thereby increasing Ca2+ influx
4. Contractor et al (2001)
   1. GluR6 knockout mice- impair synaptic facilitation
   2. presynaptic or postsynaptic?

      Nota:

      • It was possible that the observed reduction in mossy fiber LTP in the GluR6−/− mice arose either from the deficit in the presynaptic frequency response or from postsynaptic mechanisms, because GluR6-containing kainate receptors are located at both pre- and postsynaptic sites at the mossy fiber synapse

1. mGluR7 knockout

   Nota:

   • although LTP was normal in the mGluR7 knockout, there was a deficiency in STP (Bushell et al., 2002). This suggests that presynaptic mGluRs play a role in this initial presynaptic form of plasticity, although developmental consequences of the loss of mGluR7 cannot be discounted