LTD

1. depotentiation

   Nota:

   • The depression of a potentiated response we refer to as depotentiation
   • depotentiation is genuine erasure of LTP, returning the pathway to a state in which LTP can again be elicited (Dudek and Bear, 1992, 1993).
   • is controlled by different NMDA receptor subunits (NR2B for LTD and NR2A for depotentiation) (Massey et al., 2004).
   • knockout mice lacking the A catalytic subunit of calcineurin, LTD can be elicited but depotentiation cannot (Zhuo et al., 1999).
   1. LTD and depotentiation are different mechanisms

      Nota:

      • LTD and depotentiation are not the same phenomenon (in the sense that they are generated by a common mechanism) because different phosphatases are involved in the two cases (Lee et al., 2000)
2. de-depression

   Nota:

   • the repotentiation of a depressed response as de-depression
   •  true reversal or erasure of LTP, not the superposition of depression on a still potentiated background.
3. graded bidirectional synaptic modifiability

   Nota:

   • In this model, with appropriate high- or lowfrequency stimulation, a synapse could be potentiated, depotentiated, depressed, or de-depressed, thus allowing its efficacy to be set anywhere within a range of approximately 50% of its base level.
   1. Dudek and Bear, 1993
4. In-vitro
   1. First reports
      1. Dudek and Bear (1992)

         Nota:

         • Dudek and Bear (1992) (Fig. 10–17D) found that prolonged trains of LFS reliably produced LTD in young animals that experimental interest in LTD began to accelerate
      2. Dudek and Bear, 1993

         Nota:

         • LTD is routinely obtained with the Bear- Dudek protocol (typically 900 stimuli at 1Hz) only when slices are prepared from juvenile rats
5. reversible

   Nota:

   • When LTP is saturated and then depotentiated by LFS, it can subsequently be reinstated from the depotentiated level by high-frequency stimulation
6. in-vivo
   1. harder in adult animals

      Nota:

      • more difficult to obtain LTD and depotentiation in the intact adult rat than in younger animals
   2. The standard 900 pulses/1Hz protocol

      Nota:

      • has been successfully used by some
   3. higher frequencies (2–5 Hz)

      Nota:

      • others have found it necessary to use trains at higher frequencies (2–5 Hz) (Doyle et al., 1997)
7. Strain specific

   Nota:

   • There is also evidence that susceptibility to LTD is strain-specific, with Wistar and Sprague-Dawley rats showing a lower threshold for LTD than hooded Listers (Manahan-Vaughan, 2000).
8. Temporal properties
   1. LTD

      Nota:

      • LTD can persist for days in chronically implanted animals (Doyère et al., 1996),
      1. lasts days
   2. depotentiation

      Nota:

      • more than 24 hours (Kulla et al., 1999).
      1. Temporal window
         1. lasts >24hs in DG

            Nota:

            • In the dentate gyrus of the unanesthetized rat, depotentiation has been reported to persist for 24 hours (Kulla et al., 1999).
         2. DG- within minutes of LTP induction

            Nota:

            • using LFS
         3. CA1- 10min-24h of LTP induction

            Nota:

            • In area CA1 of the awake animal, however, Doyle et al. (1997), using 900 stimuli at 5 to 10 Hz, succeeded in depotentiating LTP at a range of intervals from 10 minutes to 24 hours after induction in area CA
         4. state dependence - newly unsilenced connections

            Nota:

            • between CA3 pyramidal cells in organotypic cultures In this preparation, about 20% of connected cells are originally silent (that is, the postsynaptic cell does not respond to an action potential generated in the presynaptic cell) but can be made active by an LTP-inducing pairing protocol.
            1. first few minutes- not reversible

               Nota:

               • For the first few minutes or so after unsilencing, these new functional connections are immune to re-silencing.
            2. >30min reversible

               Nota:

               • After 30 minutes, the newly activated connections enter a state in which they can be depressed by low-frequency stimulation and after LTP induction can be depotentiated in the usual way by low-frequency stimulation (Montgomery and Madison, 2002).
      2. pharmacology of depotentiation

         Nota:

         • AP5 blocks depotentiation in area CA1 in vitro (Fujii et al., 1991; Selig et al., 1995b; Huang CC et al., 2001; Lüthi et al., 2004), whereas others have found it is blocked by Gp 1/II mGluR antagonists, and not by NMDAR antagonists, in both area CA1 in acute slices (Bashir and Collingridge, 1994; Fitzjohn et al., 1998)  and between pairs of CA3 pyramidal cells in organotypic hippocampal cultures (Montgomery and Madison, 2002).
         1. blocked by NMDAR anta
         2. blocked by mGluR anta
         3. Similar to LTD- two forms exists
   3. Heterosynaptic depression

      Nota:

      • can also last for days (Abraham et al., 1994; Doyère et al., 1997)
      1. lasts days
   4. Is depotentiation and dedeprtession reversable, and time-limited?

      Nota:

      • A question of bidirectional plasticity
9. destabiization

   Nota:

   • Destabilization is a specific example of the more general phenomenon of depotentiation, which refers to the reversal of LTP at any posttetanus interval.Whereas destabilization is a robust phenomenon observed in all hippocampal pathways and at all ages, depotentiation at longer intervals after induction is less easily induced in adult animals.
10. Properties
    1. Input specific
       1. depotentiation in the CA1

          Nota:

          • CA1, depotentiation appears to be input-specific (Bortolotto et al, 1994)

1. Protocols
   1. PP vs single pulse (LSF)

      Nota:

      • The subtly different paired-pulse protocol formulated by Thiels et al. (1994), in which the interpulse interval is set at 25 ms to maximize inhibitory feedback, produces a depression that is NMDAR-dependent rather than mGluRdependent (Thiels et al, 2002).
      1. PP- interpulse interval- NMDAR LTD
      2. LSF- no interval- mGluR depdenent
   2. Agonist induced LTD
      1. mGluR agonists

         Nota:

         • Brief exposure to the group I mGluR agonist dihydroxyphenylglycine (DHPG) induces a reassuringly robust LTD in adult slice preparations in both area CA1 (Palmer et al., 1997) (Fig 10.17E) and the dentate gyrus (Camodeca et al., 1999).
   3. Stimulation induced LTD
      1. Low-frequency stimulation (LFS)
         1. 1-3 Hz

            Nota:

            • e.g., 100 stimuli at 1 Hz; 900 pulses at 1Hz
         2. Dunwiddie and Lynch (1978).- first used

            Nota:

            • The first report that LTD could be achieved with low-frequency stimulation (LFS) (e.g., 100 stimuli at 1 Hz) was published by Dunwiddie and Lynch (1978)
         3. Bear-Dudek protocol

            Nota:

            • typically 900 stimuli at 1Hz
      2. Spike timing dependent

         Nota:

         • Symmetrically placed on either side of the window of potentiation are two 20-ms intervals, between –10 and – 30 ms (AP preceding EPSP) and 10 and 30 ms (EPSP preceding AP), within which paired activity results in homosynaptic LTD. Bi and Rubin, 2005
         1. NMDAR dependent
         2. future Qs

            Nota:

            • Is spike timing-dependent LTD blocked by the same sub type selective NMDA receptor antagonists as conventional LTD? What is the age dependence of spike timing-dependent LTD? What are the relative roles of conventional LTD and spike timing-dependent LTD in the behaving animal?
         3. bidirectional plasticity
      3. Paired

         Nota:

         • requires an LFS paired with a postsynaptic hyperpolarisation?- e.g. PP-LFS and -40mV
         1. Depolarizing pulses

            Nota:

            • delivered to the postsynaptic cell to draw Ca2 into the cell via L-type Ca2 channels is itself sufficientsufficient to induce persistent LTD (Cummings et al., 1996). 
      4. Paired pulse (PP)- LFS

         Nota:

         • 2 paires of Low-frequency stimulation- pairs of stimuli at 0.5 Hz, with a 25-ms interpulse interval chosen to maximize paired-pulse depression (Thiels et al., 1994; Doyère et al., 1996)
         1. Paired-pulse depression (PPD)

            Nota:

            • using a paired-pulse stimulation protocol (LFS) demonstrated that there is a depression in the second stimulus

Nota:

• retrograde modulation

Adjunto:

• Endocannabinoids in synaptic plasticity

Adjunto:

• LTD

1. Heterosynaptic
   1. Heterosynaptic Associative LTD

      Nota:

      • it is only the synapses active at the time of induction that are depressed
      1. extremely rare-

         Nota:

         • Convincing examples of this form of LTD are rare, and it remains to be established if associative LTD exists in the hippocampus of the intact animal.
      2. CA1- pairing single stimuli to one pathway with out-ofphase brief high-frequency trains to a second pathway

         Nota:

         • A report by Stanton and Sejnowski (1989) that heterosynaptic associative LTD could be induced in area CA1 in vitro by pairing single stimuli to one pathway with out-ofphase brief high-frequency trains to a second pathway could not be replicated by Kerr and Abraham, (1993); or Paulsen et al., (1993).
         1. can't be reproduced in the CA1
         2. Reproduced in the DG in a 'priming' exp

            Nota:

            • In a variant of this protocol, Christie and Abraham (1992) reported that the lateral perforant path in the dentate gyrus of the anesthetized rat can exhibit associative LTD if it has previously been “primed” by stimulation at theta frequency (Abraham and Goddard, 1983; Christie and Abraham, 1992).
   2. LTD
      1. Lynch et al (1977)

         Nota:

         • In two-pathway experiments in area CA1 of the hippocampal slice, Lynch et al. (1977) noticed that a strong tetanus to one pathway was sometimes accompanied by a depression of the population spike in the second, nontetanized pathway. However, even when present, heterosynaptic depression rarely lasted for more than a few minutes in slices from adult animals
   3. Depotentiation
      1. Levy and Steward (1979)

         Nota:

         • Two years later, in a study in the dentate gyrus of the anesthetized rat, Levy and Steward (1979) showed that previously potentiated responses evoked by stimulation of the contralateral perforant path were depressed by tetanic stimulation of the ipsilateral perforant path
2. Homosynaptic
   1. Dudek and Bear (1992)

      Nota:

      • using a LFS they were the first to demonstrate LTD in CA1 Also demonstrated that APV an NMDAR anta blocked LTD More in younger mice 12-150 days vs 12-16 weeks
      1. LFS- led to LTD
      2. APV blocked LTD
3. Associative
4. Cerebellar
   1. Wataru et al (2011)
      1. D-serine

1. Receptor depdendent

   Nota:

   • LTD can be either NMDAR or mGluR dependent
   1. mGluRs

      Adjunto:

      • mGluR-dependent LTD
      1. families- 3 Groups

         Nota:

         • each group have a different downstream signalling mechanisms
         1. Group I +PLC

            Nota:

            • GluR1,5 Gq coupled
         2. Group II -cAMP

            Nota:

            • GluR2,3 Gi/o
         3. Group III

            Nota:

            • GluR4,6,7,8
      2. signalling

         Nota:

         • mGluRs are coupled to Gproteins, and as expected DHPG-induced LTD requires activation of G-proteins
         • How the various signalling components that have been identified in mGluR-dependent LTD (e.g., PI3K-Akt-mTOR, MAPKs, PTPs) interrelate is not known. What is clear, however, is that the signalling mechanisms involved in mGluRinduced LTD are very different from those involved in NMDAR-dependent LTD
         1. NOT involved
            1. PKC/ Ca inhibitors

               Nota:

               • variety of potent PKC inhibitors and blockers of Ca2 stores, applied alone or in combination, failed to affect DHPGinduced LTD (Camodeca et al., 1999; Schnabel et al., 2001).
            2. PKA inhibitors

               Nota:

               • DHPG-induced LTD is insensitive to inhibitors of PKA (Camodeca et al., 1999; Schnabel et al., 2001)
         2. ??
            1. CamKII inhibitors

               Nota:

               • inhibitors of CaMKII cause a modest enhancement of LTD (Schnabel et al., 1999).
            2. PTK inhibitors ??

               Nota:

               • It has been suggested that DHPG-induced LTD is blocked by PTK inhibitors in the dentate gyrus (Camodeca et al., 1999) but this finding was not replicated in area CA1 (Moult et al., 2002), suggesting the possibility of regional differences.
            3. MAPK

               Nota:

               • Whilst there is general agreement for a role of MAPK cascades, there is some contention as to whether the mechanism involves the Ras-activated ERKs (Gallagher et al., 2004) or the Rap-activated p38 MAPK (Rush et al., 2002; Huang CC et al., 2004).
            4. PKC

               Nota:

               • unlike DHPG-induced LTD, synaptically-induced mGluRdependent LTD appears also to be sensitive to PKC inhibitors (Oliet et al, 1997).
               • variety of potent PKC inhibitors and blockers of Ca2 stores, applied alone or in combination, failed to affect DHPGinduced LTD (Camodeca et al., 1999; Schnabel et al., 2001).
         3. Involved
            1. Protein phosphastases

               Nota:

               • phosphorylation is important for LTP, dephosphorylation is for LTD

               Adjunto:

               • LTD
               1. PTP

                  Nota:

                  • Protein tyrosine phosphotase
                  1. mGluR-LTD is PTP dependent
                     1. regulate AMPAR
                        1. conductance
                        2. no. of recep
                  2. Patch clamp- whole-cell recordings- PAO/OV

                     Nota:

                     • injecting the PAO/ OV intracellularly into the cell via the pipette >>blocked LTD
                  3. Moult et al 2006
                     1. mGluR (group I) agonist DHGP

                        Nota:

                        • Moult et al (2006) can induce LTD- DHPG treatment of hippocampal slices was associated with a decrease in the level of tyrosine phosphorylation of GluR2 AMPA receptor (AMPAR) subunits, an effect blocked by orthovanadate
                     2. OV- AMPAR receptor phosphorylation

                        Nota:

                        • OV- blocked the ability of DHPG to reduce the number of AMPA receptor clusters on the surface of dendrites
                  4. Moult et al (2008)
                     1. Extracellular- non-selective phosphatase inhibitor (OV)

                        Nota:

                        • Moult et al (2008) fEPSP measurements- extracellular recordings?blocks LTD after a PP-LFS stimulation protocol- 
                     2. selective inhibitor (PAO)

                        Nota:

                        • blocks LTD more than the nonselective inhibitor Moult et al (2008)
                        1. Block DHGP-LTD

                           Nota:

                           • also block the changes in paired-pulse facilitation and coefficient of variation
                  5. retrograde signalling- PTP?

                     Nota:

                     • These postsynaptic manipulations using PTP inhibitors blocked the changes in paired-pulse facilitation and miniature frequency, suggesting a retrograde signaling process that is dependent on PTPs and the actin cytoskeleton.
               2. NOT in mGluR- LTD
                  1. PP1/ PP2A

                     Nota:

                     • inhibitors of the ser/thr phosphatases that are involved in NMDAR-dependent LTD (PP1/PP2A and PP2B) do not inhibit DHPG-induced LTD; rather, PP1/PP2A inhibitors cause a small facilitation of the effect (Schnabel et al., 2001).
            2. G-proteins

               Nota:

               • DHPG-induced LTD requires activation of G-proteins (Watabe et al., 2002; Huang CC et al., 2004).
            3. PI3K-Akt mTOR

               Nota:

               • there is evidence for a role of the PI3K-AktmTOR signalling pathway in DHPG-induced LTD (Hou and Klann, 2004).
            4. Protein synthesis/ translation
               1. isolated in vitro preparation

                  Nota:

                  • mGluR-induced LTD survived in an isolated in vitro preparation, from which both pre- and postsynaptic cell bodies had been removed by appropriate scalpel cuts. This result implies that local protein synthesis at synaptic sites is required early in the expression of mGluR-induced LTD. Given that protein synthetic machinery has not been described at presynaptic boutons, it seems safe to conclude that the induction of this early form of protein synthesis-dependent LTD is located in dendrites.
               2. inhibitors

                  Nota:

                  • both DHPG- and synaptically induced LTD is blocked by protein synthesis inhibitors (Hüber et al., 2000).
      3. stimulation induced LTD
         1. PP-LFS
            1. nonspecific mGluR anta

               Nota:

               • using a paired pulse LFS protocol- they demonstrated that the application of a GluR antagonist blocked the LTD compared to controls
               1. block LTD

                  Nota:

                  • compared to controls
            2. GluR1 anta

               Nota:

               • Moult et al (2008)
               1. doesn't block LTD

                  Nota:

                  • compared to controls
            3. GluR5anta

               Nota:

               • Moult et al (2008)
               1. blocks LTD

                  Nota:

                  • compared to controls
            4. may be more NMDAR-dependent

               Nota:

               • see protocols- PP vs single pulse
            5. blocked by protein synthesis inhibitor

               Nota:

               • Synaptically driven mGluR-dependent LTD induced by low-frequency trains of paired pulses was also blocked by anisomycin (Hüber et al., 2000).
         2. LFS
            1. LTD blocked by calcium chelators

               Nota:

               • Low-frequency trains to Schaffer-commissural fibers in slices from neonatal rats induce a form of mGluR-dependent LTD that is blocked by postsynaptic injection of calcium chelators but is, at least in part, expressed as an increase in transmitter release (Bolshakov and Siegelbaum, 1994)—a combination that immediately suggests the need for a retrograde messenger
               1. there is a retrograde messenger?
                  1. possibly AA

                     Nota:

                     • lipoxygenase metabolite of arachidonic acid, 12(S)HPETE, may be the retrograde messenger in this case has been presented by Feinmark et al. (2003).
            2. in-vitro, but not in-vivo

               Nota:

               • the paired-pulse protocol introduced by Kemp et al. (2000) (900 pairs at 1 Hz with an interpulse interval of 50 msec) generates mGluR-dependent LTD in area CA1 in vitro (see also Hüber et al., 2000), it has not been shown to be effective in vivo
         3. Group I vs II anta

            Nota:

            • although group I mGluR antagonists are generally more effective at blocking mGluR-dependent LTD in area CA1 in vitro, group II antagonists depress the late component of LTD in vivo (Manahan- Vaughan, 1997).
      4. Agonist induced LTD

         Nota:

         • inducing LTD via the application of mGluR agonists and using various pharmacological methods to study the mechanims
         1. group I mGluR agonist (DHPG)

            Nota:

            • Brief exposure to the group I mGluR agonist dihydroxyphenylglycine (DHPG) induces a reassuringly robust LTD in adult slice preparations in both area CA1 (Palmer et al., 1997) (Fig 10.17E) and the dentate gyrus (Camodeca et al., 1999).
            1. CA1
            2. DG
            3. blocked by mGluR anta (specigic/non-), bu not NMDAR anta

               Nota:

               • This form of LTD, probably mediated by mGluR5 receptors, is blocked by group I or broad-spectrum mGluR antagonists but not by NMDA receptor antagonists
            4. G protein inhibitor- blocked LTD induction

               Nota:

               • Intracellular injection of a G protein inhibitor into CA1 pyramidal cells suppressed the ability of DHPG to induce LTD (Watabe et al., 2002).
            5. Intracellular injection of BAPTA, (Ca chelator)

               Nota:

               • Intracellular injection of BAPTA, on the other hand, doesn't block LTD (Fitzjohn et al., 2001b),
            6. Protein synthesis inhibitor- reduced LTD

               Nota:

               • In the presence of the protein synthesis inhibitor anisomycin, the depression induced by DHPG quickly attenuates, and responses recover to baseline within 60 minutes (Hüber et al., 2000).
      5. Locus of expression
         1. presynaptic

            Nota:

            • in mGluRLTD there was reduction in miniature frequency, with no change in quantal size, suggesting a presynaptic expression mechanism.
            1. photolysis of caged glutamate

               Nota:

               • there is no postsynaptic change in response to flash photolysis of caged glutamate (Rammes et al., 2003),
               1. AMPAR diffused?

                  Nota:

                  • The lack of change in the response to uncaged glutamate, which act on both spines and dendrites, can be reconciled with a postsynaptic model if, instead of being internalized, AMPA receptors diffuse laterally to extrasynaptic sites (Moult et al., 2006).
            2. NMDAR and AMPAR responses

               Nota:

               • NMDA and AMPA receptor components of synaptic responses are equally depressed (Watabe et al., 2002),
            3. increased PPF

               Nota:

               • paired-pulse facilitation is increased (Fitzjohn et al., 2001)
            4. decrease in frequency, not amplitude of mEPSCs

               Nota:

               • pulse facilitation is increased (Fitzjohn et al., 2001), and (4) DHPG produces a persistent decrease in the frequency of miniature EPSCs with no change in amplitude in tetrodotoxin-treated cultured hippocampal neurons (Fitzjohn et al., 2001b).
            5. AMPAR removed- silent synapses?

               Nota:

               • An alternative explanation is that AMPA receptors are removed to create silent synapses. If this occurs preferentially at high-Pr synapses owing to the requirement for activity to drive the movement, the changes in paired-pulse facilitation would simply reflect this postsynaptic alteration
         2. postsynaptic
            1. receptors trafficking

               Nota:

               • evidence that DHPG-induced LTD involves removal of both AMPA and NMDA receptors from synapses (Snyder et al., 2001).
            2. PTP inhibitors- postsynaptic

               Nota:

               • mGluR-dependent LTD, induced by DHPG, is blocked by postsynaptically applied inhibitors of protein tyrosine phosphatases (PTPs) and of the actin cytoskeleton (Moult et al,2006)
               1. retrograde signalling mediated by PRP

                  Nota:

                  • These postsynaptic manipulations using PTP inhibitors blocked the changes in paired-pulse facilitation and miniature frequency, suggesting a retrograde signaling process that is dependent on PTPs and the actin cytoskeleton.
   2. NMDAR
      1. Induction
         1. LTD blocked by NMDAR anta (APV)

            Nota:

            • Long-term depression is defined as NMDAR-dependent if it is blocked by D-AP5 or other NMDA antagonists
         2. Conditions for NMDAR-dependent LTD induction
            1. requires a rise in postsynaptic Ca2
               1. Ca2 chelator

                  Nota:

                  • induction of LTD can be prevented by dialyzing CA1 pyramidal cells with a Ca2 chelator (Mulkey and Malenka, 1992).
               2. lowering external Ca

                  Nota:

                  • lowering external Ca2 transforms a protocol that normally induces LTP into one that produces LTD (Mulkey and Malenka, 1992).
               3. reducing Ca enter- using APV

                  Nota:

                  • lowering external Ca2 transforms a protocol that normally induces LTP into one that produces LTD (Mulkey and Malenka, 1992).
               4. small, prolonged increases

                  Nota:

                  • lower Ca2 charge transfer through the NMDA receptor channel is associated with LTD and higher transfer with LTP (Cho et al., 2001;Wu et al., 2001).
            2. Activation of phosphatases

               Nota:

               • This suggests a potential mechanism whereby low elevations of Ca2 activate protein phosphatases to yield LTD, whereas higher concentrations activate protein kinases to yield LTP
               1. high affinity for Ca

                  Nota:

                  • protein phosphatases have a higher affinity for Ca2 than most protein kinases.
               2. PPI

                  Nota:

                  • protein phosphotase
            3. Lisman hypothesis- mechanism

               Nota:

               • Lisman (1989) activation of the Ca2-sensitive protein phosphatase calcineurin (also known as protein phosphatase 2B, or PP2B). Activated calcineurin then dephosphorylates a phos-phoprotein called inhibitor 1 (I1), which in its activated state inhibits PP1. Activation of calcineurin thus leads to the activation of PP1 by disinhibition, allowing CaMKII to be dephosphorylated. A critical feature of this scheme is that calcineurin has a higher sensitivity for Ca2 than CaMKII, consistent with the hypothesis that small increases in intracellular Ca2 lead to LTD and larger increases to LTP. Note also that the scheme provides for a feedback, or gating, mechanism in which the PKA/inhibitor 1 pathway counteracts the effects of the calcineurin pathway when Ca2 levels rise to levels that lead to autophosphorylation of CaMKII and LTP
               1. (+) specific PP1, PP2B inhibitors

                  Nota:

                  • LTD was blocked by injecting specific inhibitors of PP1 and PP2B (calcineuri) into CA1 neurons (Mulkey et al., 1993, 1994).
               2. (-) transgenic mice expression PP2B inhibitor

                  Nota:

                  • transgenic mice expressing an inducible calcineurin inhibitor failed to confirm the importance of calcineurin for LTD; although LTP was enhanced, LTD was not affected (Malleret et al., 2001), suggesting either that the inhibitors were acting on another phosphatase or that another high-affinity phosphatase can take over the role normally played by calcineurin.
                  1. other phosphotases
               3. (+) phosphotases high Ca affinity
               4. (+) small prolonged increases in Ca-LTD

                  Nota:

                  • lower Ca2 charge transfer through the NMDA receptor channel is associated with LTD and higher transfer with LTP (Cho et al., 2001;Wu et al., 2001).
                  • Mizuno et al. (2001); pharmacological manipulations were used to control the magnitude of the Ca2 transient produced by 1 Hz stimulation, but under no circumstances were trains of less than 200 stimuli successful in inducing LTD
         3. subtypes

            Nota:

            • The NMDA receptor forms a heterotetramer between two GluN1 and two GluN2 subunits (the subunits were previously denoted as NR1 and NR2); two obligatory NR1 subunits and two regionally localized NR2 subunits. 
            1. NR2
               1. NR2B ?
                  1. knockouts

                     Nota:

                     • Kutsuwada et al., 1996
                     1. lacked LTD, developmental problems

                        Nota:

                        • These animals lacked LTD but had major developmental problems and died young
                  2. specific anta
                     1. LTD is enhanced

                        Nota:

                        • LTD is reported to be enhanced by NR2B inhibitors (Hendricson et al., 2002)
                     2. LTD is blocked

                        Nota:

                        • other blocked by these compounds (Liu et al., 2004a)
               2. NR2D
                  1. Pharmacological evidence

                     Nota:

                     • Other pharmacological evidence has instead provided evidence for a role of NR2C and/or NR2D receptors in LTD (Hrabetova et al., 2000).
                  2. slow component of synaptic response

                     Nota:

                     • There is also evidence that NR2D receptors can mediate a very slow component of the synaptic response at hippocampal synapses (Lozovaya et al., 2004). The very slow kinetics of this channel coupled with its low sensitivity to Mg2 means that the NR2D component of the NMDAR-mediated EPSC will summate effectively at the low frequencies of stimulation that are typically used to induce LTD
               3. NR2A:NR2B subunit ratio

                  Nota:

                  • The NR2A:NR2B subunit ratio of the NMDA receptors is widely known to increase in the brain from postnatal development to sexual maturity and to aging, yet its impact on memory function remains speculative
                  1. Cui et al (2013)
                  2. NR2A-overexpressed- transgenic mice

                     Nota:

                     • We have generated forebrain-specific NR2A overexpression transgenic mice and show that these mice had normal basic behaviors and short-term memory, but exhibited broad long-term memory deficits as revealed by several behavioral paradigms. 
                     1. Long-term memory deficits
                     2. LTD

                        Nota:

                        • increased NR2A expression did not affect 1-Hz-induced long-term depression (LTD) or 100 Hz-induced long-term potentiation (LTP) in the CA1 region of the hippocampus, but selectively abolished LTD responses in the 3–5 Hz frequency range
      2. Expression
         1. AMPAR modification
            1. reversal of AMPAR phospho by PP1/ PP2A

               Nota:

               • High-frequency stimulation leads to activation of CaMKII and phosphorylation of ser831, a state associated with increased single-channel conductance of the receptor (Derkach et al., 1999). Depotentiation by lowfrequency stimulation reverses this process by activation of protein phosphatases PP1 and PP2A.
         2. downregulation of AMPAR/ NMDAR
            1. photolytic uncaging of caged glutamate

               Nota:

               • Kandler et al., 1998; Rammes et al., 2003
            2. iontophoresis of NMDA

               Nota:

               • Montgomery and Madison, 2002
            3. immunocytochemistry
               1. AMPAR and NMDAR- in-vivo- following LTD induction

                  Nota:

                  • immunocytochemical estimates of both AMPA and NMDA populations in tissue from animals in which LTD was induced in vivo (Heynen et al., 2000).
               2. AMPAR- during LTD

                  Nota:

                  • direct demonstration of AMPA receptor internalization during LTD in cultured hippocampal neurons (Beattie et al., 2000).
         3. regulation of AMPAR subunit GluR2
            1. Mechanism

               Nota:

               • a mechanism whereby NSF is normally bound to GluR2 subunits to stabilize AMPA receptors at the synapse. However, in response to an LTD-inducing stimulus, AP2 exchanges with NSF, and this initiates clathrindependent endocytosis (Collingridge et al., 2004). This scheme requires a mechanism to initiate the exchange of NSF for AP2. One possibility is that Ca2 entry during the induction of LTD interacts with the neuronal Ca2 sensor hippocalcin (Burgoyne, 2004). On binding Ca2, hippocalcin undergoes a conformational change to expose a myristoylated region that can target the molecule to the plasma membrane. It also binds both AP2 and GluR2 subunits in a Ca2-dependent manner (Palmer et al, 2005). Thus, hippocalcin is well placed to actively promote the exchange of NSF for AP2.
               1. NSF
                  1. NSF binds selectively to the GluR2 subunit

                     Nota:

                     • The concept of subunitdependent regulation of synaptic plasticity arose from the finding that NSF binds selectively to the GluR2 subunit of AMPA receptors (Nishimune et al., 1998; Osten et al., 1998; Song et al., 1998).
                     1. first evidence for role of GluR2
                  2. blockade of the GluR2 interaction with NSF

                     Nota:

                     • leads to a run-down in AMPAR-mediated synaptic transmission (Nishimune et al., 1998; Song et al., 1998), a reduction in the surface expression of AMPA receptors (Lüscher et al., 1999; Noel et al; 1999), and occlusion with NMDAR-dependent LTD (Lüscher et al., 1999; Lüthi et al., 1999).
                     1. reduced synaptic transmission
                     2. reduction in AMPAR surface expression
                     3. block LTD
               2. AP2

                  Nota:

                  • AP2 binds to a region of GluR2 that overlaps with the NSF site(Lee et al., 2002).
                  1. block of the GluR2 interaction with AP2
                     1. block LTD
               3. Ca sensor- hippocalcin
                  1. dominant negative form- blocks induction

                     Nota:

                     • dominant negative form of hippocalcin blocks induction of NMDAR-dependent LTD (Palmer et al, 2005). Thus, hippocalcin is a strong contender for the role of Ca2 sensor in LTD. It is likely, however, that other Ca2-sensing proteins are also involved in the induction of LTD, and the full mechanistic details have yet to be elucidated.
                     • dominant negative form of hippocalcin blocks induction of NMDAR-dependent LTD (Palmer et al, 2005). Thus, hippocalcin is a strong contender for the role of Ca2 sensor in LTD. It is likely, however, that other Ca2-sensing proteins are also involved in the induction of LTD, and the full mechanistic details have yet to be elucidated.
                  2. other sensors likely
               4. Scaffolding proteins

                  Nota:

                  • Scaffolding proteins such as GRIP/ABP (Dong et al., 1997; Srivastava and Ziff, 1999) and the PKC-targeting protein PICK (Dev et al., 1999; Xia et al., 1999) also bind to the C terminal tail of the GluR2 subunit, where they may tether AMPA receptors at the plasma membrane or at intracellular sites.
                  1. GRIP/ABP
                     1. evidence for the their role in expression of LTP
                  2. PKC-targeting protein (PICK)
                     1. PICK1 binds Ca2, facilitating its interaction with AMPA receptors

                        Nota:

                        • Hanley and Hanley, 2005
                     2. Ca2-insensitive PICK1 mutant

                        Nota:

                        • blocks NMDA-induced internalization of AMPA receptors, implicating this interaction in LTD
                  3. mechanism 1

                     Nota:

                     • The proposal is that GRIP/ABP normally anchors AMPA receptors at the synapse. However, LTD leads to activation of PICK1, which phosphorylates GluR2 subunits, causing them to dissociate from GRIP/ABP so they can be removed from the synapse.
                     1. Both?

                        Nota:

                        • It is possible that these diametrically opposed roles of PICK1, via its interaction with GRIP/ABP, can both operate under different conditions.
                     2. GRIP/ ABP anchor AMPAR?
                  4. mechanism 2

                     Nota:

                     • another idea is that GRIP/ABP binds the GluR2 subunit to maintain a store of AMPA receptors intracellularly (Daw et al., 2000). In this scheme, when PICK1 phosphorylates GluR2 it untethers AMPA receptors and so provides a pool near the synapse, ready for membrane insertion. It is possible that these diametrically opposed roles of PICK1, via its interaction with GRIP/ABP, can both operate under different conditions.
                     2. GRIP/ ABP maintain an AMPAR intracellular store?
            2. GluR2 knockout and the GluR2/GluR3 double knockout

               Nota:

               • NMDAR-dependent LTD has been observed in both the GluR2 knockout and the GluR2/GluR3 double knockout (Jia et al., 1996; Meng et al., 2003).
            3. GluR1??

               Nota:

               •  Moreover, as we have seen, the dephosphorylation of ser845 of GluR1 can also result in LTD (Kameyama et al., 1998), suggesting that there are multiple mechanisms for the induction of LTD.
         4. Protein synthesis
            1. protein synthesis inhibitors

               Nota:

               • Different preparations were used in each of these studies: organotypic cultures (Kauderer and Kandel, 2000), acute slices (Hüber et al., 2000), and freely moving rats (Manahan-Vaughan et al., 2000). In all three preparations, late LTD lasting several hours could be induced by prolonged low-frequency stimulation, and in each case it was blocked by protein synthesis inhibitors.
            2. translation inhibitors

               Nota:

               • However, only in organotypic culture was late LTD blocked by transcriptional inhibitors.
         5. Inhibition of actin depolymerisation
            1. block NMDAR LTD, but not AMPAR
      3. postsynaptic

         Nota:

         • Oliet et al. (1997) also observed a decrease in the quantal size of miniature EPSCs without a change in miniature frequency in NMDAR-dependent LTD, suggesting a postsynaptic expression mechanism
   3. AMPAR
      1. PP2B inhibitors

         Nota:

         • calcineurin blocked LTD  of AMPAR EPSCs but not LTD of NMDAR EPSCs
      2. dynamin-dependent endocytosis
         1. in-vivo- dominant negative

            Nota:

            • an HPC slice was injected with a sindbis virus encoding a dominant-negative form of dynamin 1- coupled with GFP- blocked LTD of AMPARS EPSCs, but not NMDAR
         2. inhibitors

            Nota:

            • inhibitors of dynamin-dependent endocytosis blocks AMPAR EPSCs, but not NMDAR EPSCs
2. Controversy- is LTD mGluR or NMDAR dependent
   1. Oliet et al. (1997)

      Nota:

      • showed that it was possible to obtain either result by manipulating the induction protocol, thus confirming the existence of two independent forms of homosynaptic LTD.
3. Type specific

   Nota:

   • These experiments confirmed the existence of two distinct types of LTD at Schaffer-commissural–CA1 pyramidal synapses with distinct induction and expression mechanisms

1. Diseases - Luscher & Huber, 2010

   Nota:

   • mGluR LTD is region dependent- different 

   Adjunto:

   • LTD
   1. Alzheimer's- cortex
   2. Fragile X- cerebellum and cortex
   3. Parkinson's- straitum
   4. Cocaine- Accumbens
   5. Drug addiction- VTA
2. Hippocampal LTD

   Nota:

   • Thus, the influences of novelty and stress on hippocampal LTD seem to be remarkably similar. What these two conditions have in common, perhaps, are that they are both anxiety-provoking experiences and therefore activate the same stress-responsive neuroendocrine systems
   • The reversal of LTP (depotentiation) is an adaptive response in which exploration, novelty or stress resets previously induced plastic changes to facilitate the generation of new information through LTP
   1. Novel- in rats
      1. Novel, enriched environment
         1. HFS-induced LTP is revered

            Nota:

            •  In CA1, LTP produced by HFS (200 Hz) is completely reversed (‘depotentiated’) when rats are allowed to explore a novel, but not familiar, environment 38 and 39. 
         2. LFS-induced LTD is facilitated

            Nota:

            • Similarly, in the CA1 region, LTD is facilitated when LFS (1 Hz; 900 pulses) is delivered during active exploration of a novel, stimulus-rich environment
         3. LTP and LTD were both enhanced

            Nota:

            • hippocampal brain slices taken from rats exposed to an ‘enriched environment’, LTP and LTD were both enhanced after 3–5 weeks
      2. Novel objects
         1. facilitatied LTD, impaired LTP
      3. novel environment alone

         Nota:

         • environment alone (with no objects), impairs LTD and facilitates LTP
         1. impairs LTD and facilitates LTP
   2. in vivo electrophysiological recording in freely moving rats
   3. Stress- adult rats
      1. acute and prolonged exposure- cognitive deficits
      2. impairs LTP, facilitates LTD

         Nota:

         • This effect is robust and durable enough to be observed in hippocampal slices taken from rats 7–9 months after exposure to behavioural stress
      3. corticosteroid hormones
         1. facilitates LTD

            Nota:

            • by inducing a long-lasting depression of glutamate uptake mechanisms. This results in greater spillover of glutamate, activation of extrasynaptic NR2B-containing NMDA receptors and, thus, facilitation of LTD
3. Cerebellar LTD
   1. Parallel fibre–PC synapse LTD
      1. mGluR-dependent, NOT NMDAR
         1. PKC>> phosphorylation at Ser880 GluRq2 (AMPAR)
            1. removed GRIP from GluR2

               Nota:

               • It is thought that phosphorylation at Ser880 removes GRIP from GluR2, and that this is a key trigger for internalization of GluR2
               1. internalisation of AMPAR
         2. different to hippocampal mGluR LTD

            Nota:

            • The involvement of protein kinase C in cerebellar LTD, rather than protein phosphatases, as in other brain regions, highlights the possibility that AMPA receptor endocytosis mechanisms might be cell-type specific, perhaps depending on the constituent AMPA receptor subunits and their associated proteins
            1. LTD is cell specific?
   2. LTD is really causally related to motor learning in the cerebellum? Debated
      1. prevention of PC LTD does not affect locomotor learning or eyeblink conditioning
4. Striatal LTD
5. Visual cortex
6. Perirhinal cortex