Expression of LTP

Anlagen:

• Expression of LTP

1. increase Pr
   1. decrease in failure rate
      1. Stevns and Wang (1994)

         Anmerkungen:

         • in the experiment the amplitude of responses increased following LTP induction and was correlated with decrease in failure rate (increased Pr). Furthermore, there was no change in potency (average amplitude induced by successes)>> suggesting the increase of overall amplitude (or efficacy) was due to decrease in failure rate
   2. Enoki et al (2009)
      1. optical quantal analysis

         Anmerkungen:

         • measured Pr using imaging techniques- increase in fluoro when there is transmission
      2. following LTP induction- no change in potency

         Anmerkungen:

         • but there was a change in Pr
2. increase in release sites
3. increase in transmitter release

   Anmerkungen:

   • Both showed a correlation of Glu release with LTP
   1. increase in cleft [glu]

      Anmerkungen:

      • glutamate
      1. Choi et al (2000)??
         1. competitive anta with low affinity

            Anmerkungen:

            • if there is high glu conc then more glu will bind to the receptors than the anta (high-affinity anta won't work because it will always bind to the receptors)
            • before LTP induction the application of L-AP5 (low affinity competitive anta) decreased NMDA EPSP almost completely, Following LTP induction L-AP5 reduced the EPSP less- showing that more glu bound to the receptors than the anta
   2. Dolphin et al (1982)
   3. Bliss et al (1986)
   4. vesicle release
      1. increase in vesicle recycling
         1. Malgaroli et al (1995)
            1. immunocytochemistry
4. STP/ early-LTP

Anlagen:

• Expression of LTP

1. Receptors

   Anlagen:

   • Expression of LTP
   1. increase in no.
      1. unsilenced synapses
         1. AMPAR
            1. Isaac et al (1995)
      2. insertion of additional receptors
         1. AMPAR
            1. via CaMKII
               1. Hayashi et al (2000)
            2. antibody labelling

               Anmerkungen:

               • of live neurons in the hippocampus
               1. Pickard et al (2001)
      3. growth of synapse with insertion of additional release sites and receptors
   2. increased efficiency/ potency

      Anmerkungen:

      • potency= amplitude of responses; only successes
      1. increase in P(o)

         Anmerkungen:

         • probability of opening
      2. Increase channel open time
         1. No evidence for this
      3. increase in conductance

         Anmerkungen:

         • passes more current in the same time
         1. Benke et al (1998)
            1. single channel conductance
         2. Derkach et al., 1999

            Anmerkungen:

            • 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).
      4. Benke et al (1998)

         Anmerkungen:

         • following a pairing stimulus a decrease in mean amplitude of sucesses
   3. Changes to receptors
      1. mGluR
         1. GluA1
            1. GluA1 knockout mice

               Anmerkungen:

               • no LTP in knockout mice
               1. Zamanillo et al (1999)
            2. GluA1 + CamKII

               Anmerkungen:

               • CaMKII phosphrylates GluA1
            3. Ser81 site mutant
               1. Derkach et al (1999)
            4. antibody labelling
      2. AMPAR
         1. CamKII
         2. increase in no.
         3. stabilization via NSF binding to GluA2
            1. Nishimune et al (1998)
         4. PKM mRNA
2. early- late-LTP
3. Evidence that LTP can occur without presynaptic
   1. McNaughton (1982)
      1. no change in PPR

         Anmerkungen:

         • therefore no change in Pr
4. Effectors- Early LTP

   Anmerkungen:

   • minutes-hours
   1. CaMKII

      Anmerkungen:

      • Calcium/calmodulin-dependent protein kinase II (CaMKII) is a major component of the postsynaptic density, comprising 2% of its protein content (Lisman et al., 2002).
      • Following a transient surge in calcium concentration, intramolecular autophosphorylation at threonine 286 can occur, producing a conformation that allows the enzyme to remain autonomously active when calcium levels fall, thereby endowing the enzyme with the properties of a molecular switch
      1. general

         Anmerkungen:

         • consists of dodecamers (12 protein subunits) of beta and alpha subunits. In its inactive state, the ATP binding site of the catalytic region of the enzyme is bound to an autoinhibitory domain in the regulatory region. When calcium-loaded calmodulin binds to a calmodulin-binding region in the 3′ region of the molecule, a conformational change occurs that separates the autoinhibitory domain from the ATP binding site and renders the enzyme active.
      2. isoforms
         1. alpha CaMKII

            Anmerkungen:

            • the dominant form in area CA1 is alpha CaMKII
            1. specific peptide inhibitors
               1. Malinow et al., 1989

                  Anmerkungen:

                  • block induction of LTP
                  1. (-) background effects

                     Anmerkungen:

                     • although there may be a background effect contributing to this deficit (Hinds et al., 1998).
            2. membrane permeable CaMKII inhibitors

               Anmerkungen:

               • KN-62 and KN-93
               1. Ito et al., 1991

                  Anmerkungen:

                  • block induction of LTP in a reversible manner
            3. knockouts
               1. Silva et al., 1992b

                  Anmerkungen:

                  • LTP is impaired in alphaCaMKII–/– mice
         2. beta
      3. mutation at residue 286

         Anmerkungen:

         • mice with a threonine to alanine point mutation at residue 286 that prevents autophosphorylation
         1. Giese et al., 1998

            Anmerkungen:

            • do not display LTP in area CA1
      4. AMPAR
         1. drives AMPAR insertion
         2. phosphorylates AMPAR
            1. Fukunaga et al., 1995
      5. induction of LTP

         Anmerkungen:

         • Although there is general agreement that the induction of LTP is associated with a persistent ( 1 hour) phosphorylation of CaMKII, there is disagreement about whether the increase in enzyme activity is transient (Lengyel et al., 2004) or persistent (Fukunaga et al., 1995).
         1. persistent alphaCaMKII phospho
         2. transient

            Anmerkungen:

            • lasting a short time
         3. (-) inhibitors
            1. Yasuda et al., 2003

               Anmerkungen:

               • CaMKII inhibitors have no effect on the induction of LTP
      6. maintainance

         Anmerkungen:

         • Based on this evidence-  whilst persistent re-activation of the enzyme can be discounted as a mechanism it is possible that a constitutively active form of CaMKII maintains LTP.
         1. Inhibitors of CaMKII
            1. Ito et al., 1991; Chen et al., 2001b

               Anmerkungen:

               • Inhibitors of CaMKII applied following the induction of LTP have no effect However, these inhibitors compete with the calmodulin binding site, and hence the Ca2/calmodulin-dependent activation of the enzyme, but do not affect the constitutively active form.
      7. parallel pathways- MAP and PKA

         Anmerkungen:

         • in juvenile CA1, there is evidence for involvement of CaMKII as part of a parallel pathway also involving PKA and MAPK (Cooke et al, 2006;
      8. metaplasticity

         Anmerkungen:

         • CaMKII is involved in metaplasticity in area CA1 (Bortolotto & Collingridge, 1998) and so biochemical changes that accompany LTP may relate to metaplasticity rather than the plasticity per se (see Abraham and Tate, 1997).
   2. NSF
   3. PKM mRNA
      1. Yao et al (2008)
      2. Ling et al (2002)
   4. PKC

      Anmerkungen:

      • first implicated protein kinase Based on the evidence it's likley that PKC may only be involved in some, but not all aspects of early LTP, and isoforms-dependent
      1. nonspecific inhibitors
         1. (-) other kinases

            Anmerkungen:

            • effects observed may have been via actions on other kinases
         2. bock LTP
            1. Lovinger et al., 1987
      2. specific inhibitors
         1. no effect on LTP
            1. Muller et al., 1992; Bortolotto and Collingridge, 2000
         2. during de-depression

            Anmerkungen:

            • selective (though not totally specific) PKC inhibitors  de-depression- (the tetanus-induced restoration of the response in a pathway inwhich LTD has previously been induced)
      3. peptide inhibitors applied intracellularly
         1. block LTP
            1. Malinow et al., 1989
      4. multiple isoforms

         Anmerkungen:

         • Understanding the role of PKC in LTP is complicated by the existence of multiple isoforms
         1. Ca2, diacylglycerol-activated

            Anmerkungen:

            • conventional PKCs (cPKCs: alpha ,betaI, bII ,gamma );
            1. elimination of PKC(gamma)
               1. Abeliovich et al., 1993

                  Anmerkungen:

                  • inhibit LTP, although not if the LTP is preceded by low-frequency stimulation This suggests that PKC may play a regulatory role in the induction of LTP
         2. Ca-independent, diacylglycerol-activated,

            Anmerkungen:

            •  novel PKCs (nPKCs: , , , θ)
         3. diacylglycerol-independent

            Anmerkungen:

            • atypical PKCs (aPKCs: ζ, ).
            1. PKC ζ
               1. Ling et al., 2002; Serrano et al., 2005

                  Anmerkungen:

                  • a peptide substrate inhibitor of PKMζ, the autonomously active catalytic domain of PKCζ, blocks the expression of pre-established L-LTP Bath application of the inhibitor at the time of the tetanus has no effect on ELTP but blocks the development of L-LTP.
                  1. role in L-LTP
      5. trigger for induction of PKC LTP

         Anmerkungen:

         • The trigger for the induction of PKC-dependent potentiation may be Ca2 entering via NMDA receptors.An alternative route is via glutamate binding to group I mGluRs (mGluR1 and mGluR5), the activation of which leads to production of diacylglycerol and release of Ca2 from intracellular stores— the two triggers for activation of cPKCs. In this context, potent PKC inhibitors prevent mGluR-mediated metaplasticity
         1. Bortolotto and Collingridge, 2000
   5. Tyrosine kinases (PTK)

      Anmerkungen:

      • Various nonreceptor tyrosine kinases are expressed in the central nervous system, including src and the src family members fyn and lyn
      1. nonspecific PTK inhibitors
         1. necessary for E-LTP
            1. O’Dell et al., 1991a
      2. fyn

         Anmerkungen:

         • Fyn is a tyrosine-specific phospho-transferase that is a member of the Src family oftyrosine protein kinases The role of fyn appears to be developmentally regulated, as no LTP deficits are seen in animals at less than 14 weeks. 
         1. regulatory molecule

            Anmerkungen:

            • Fyn probably acts as a regulatory molecule, as LTP can be induced in the fyn knockout when a strong induction protocol is used.
            1. knockouts of fyn
               1. O’Dell et al., 1991a

                  Anmerkungen:

                  • Genetic elimination of fyn resulted in a deficit in LTP (O’Dell et al., 1991a). 
                  1. Kojima et al., 1997

                     Anmerkungen:

                     • Although this knockout was associated with gross structural changes in the dentate gyrus, a successful rescue experiment suggested that the LTP deficit reflected the loss of fyn in the adult, rather than impaired neuronal development
            2. regulates LTP is via phosphorylation of NMDARs
               1. Rosenblum et al., 1996; Rostas et al., 1996
   6. MAP kinase

      Anmerkungen:

      • mitogen-associated protein (MAP) kinase cascades that carry extracellular signals to the nucleus: inititiated by the small G proteins Ras and Rap-1.
      • The ERK/MAP kinase pathway can be positively regulated by PKA via the Rap-1, B-raf pathway and by PKC via the Ras, Raf-1 pathway. PKA can also inhibit the latter pathway
      1. specific inhibitors

         Anmerkungen:

         • Three specific inhibitors are available— PD098059, U0126, SL327—the last of which can cross the blood-brain barrier
      2. pathway
         1. Ras

            Anmerkungen:

            • G-protein- activates Raf-1
            1. Raf-1

               Anmerkungen:

               • MAP kinases
            2. Zhu et al., 2002
               1. implicated AMPAR
         2. Rap-1

            Anmerkungen:

            • G-protein- activate B-raf
            1. B-Raf

               Anmerkungen:

               • MAP kinases
               1. MEK

                  Anmerkungen:

                  • MAP kinase kinase, which in turn phosphorylates a pair of MAP kinases known as extracellular regulated kinases 1 and 2
                  1. ERK1,/2

                     Anmerkungen:

                     • extracellular regulated kinases 1 and 2
                     1. LTP induction
                        1. English and Sweatt, 1996

                           Anmerkungen:

                           • found that LTP-inducing stimuli resulted in increased phosphorylation of ERK1, 2
                  2. MEK inhibitors-
                     1. English and Sweatt, 1997

                        Anmerkungen:

                        • blocked both ELTP and L-LTP in area CA1 of hippocampal slices
                     2. stimuli protocol dependent

                        Anmerkungen:

                        • MEK inhibitors blocked induction of a form of theta-induced LTP but did not affect pairing-induced or tetanus-induced LTP (Opazo et al., 2003).
                  3. MEK transgenic mouse
                     1. Kelleher et al. (2004b)

                        Anmerkungen:

                        • found that LTP in a transgenic mouse expressing a dominant negative MEK was indistinguishable from E-LTP generated in normal mice in the presence of protein synthesis inhibitors; they concluded that the main substrates of the MAP kinase pathway were kinases regulating the protein translational machinery in dendrites.
                        1. MAP-pathway regulate protein translation
            2. Zhu et al., 2002

               Anmerkungen:

               • implicated in AMPA receptor trafficking in LTP, and another G protein, Rap, which activates a member of the ERK family, p38, is involved in the removal of AMPA receptors from synapses during LTD
      3. Yuan et al., 2002
         1. downregulate K-channel

            Anmerkungen:

            • activation of MAP kinase through PKA and PKC can downregulate a dendritic A-type K channel in CA1 pyramidal neurons, leading to a reduction in the threshold for back-propagation and potential enhancement of LTP
   7. PI3 kinase

      Anmerkungen:

      • PI3K phosphorylates PIP3 which in turn can activate Ca2-independent isoforms of PKC, PKB,and phospholipase C.
      1. inhibitors
         1. Kelly and Lynch, 2000

            Anmerkungen:

            • PI3K was first implicated in NMDARdependent LTP in the dentate gyrus, where it was shown that the inhibitor wortmannin inhibited E-LTP but not STP at perforant path synapses
            1. E-LTP
         2. Raymond et al., 2002

            Anmerkungen:

            • inhibition of E-LTP but not STP was observed at CA1 synapses using a different PI3K inhibitor, LY294002
            1. blocked E-LTP, not STP
         3. Horwood et al., 2006

            Anmerkungen:

            • In the dentate gyrus in vivo, this inhibitor blocked E-LTP induced by single but not multiple trains, suggesting that P13K is not an obligatory enzyme in LTP induction
            1. in-vivo
         4. Sanna et al., 2002

            Anmerkungen:

            • PI3K may be required specifically for the expression of LTP, as inhibition of the enzyme led to depression of preestablished LTP and, following washout of the inhibitor, recovery of LTP to its initial level
            1. reduce preestablished LTP, possible recovery
      2. downstream

         Anmerkungen:

         • The downstream processes modulated by PI3K are not known but may involve both MAPK-dependent and MAPK-independent pathways (Opazo et al., 2003) that affect the surface expression of AMPARs (Man et al., 2003).
         1. MAP
         2. AMPAR
   8. multiple and parallel kinase cascades

      Anlagen:

      • Expression of LTP
   9. PKA
      1. PKA inhibitors

         Anmerkungen:

         • via an action in the postsynaptic neuron
         1. block L-LTP
            1. Matthies and Reymann, 1993; Huang and Kandel, 1994
         2. don't block E-LTP
            1. Matthies and Reymann, 1993; Huang and Kandel, 1994
         3. (-) don't block L-LTP
            1. Bortolotto and Collingridge, 2000

               Anmerkungen:

               • LTP lasting many hours can be induced in the presence of PKA inhibitors
         4. (-) block E-LTP
            1. Huang and Kandel, 1994; Blitzer etal., 1995; Otmakhova et al., 2000

               Anmerkungen:

               • E-LTP is affected by PKA inhibitors in some cases
      2. (-) factors

         Anmerkungen:

         • It seems that the role of PKA is determined by a variety of factors, such as the strength and patterns of the high-frequency trains used to induce LTP.
         1. strong induction protocols

            Anmerkungen:

            • PKA inhibitors are more effective when strong induction protocols are used (Nguyen and Woo, 2003).
         2. early in development

            Anmerkungen:

            • more effective early in development, before the CaMKII-dependent form of LTP is expressed (Yasuda et al., 2003).
         3. sensitivity of E-LTP to PKA inhibitors- metaplasticity

            Anmerkungen:

            • is also dependent on the prior level of experience of the animal, such that environmental enrichment results in a larger LTP with the additional component being selectively sensitive to PKA inhibition (Duffy et al., 2001).
      3. cAMP analogue

         Anmerkungen:

         • cAMP induces the activation of mainly PKA- but also other transcription factors like CREB, epac etc- 
         1. (-) confounding

            Anmerkungen:

            • effects of other transcription factors on LTP- not a direct measure for testing PKA
         2. Frey et al., 1993

            Anmerkungen:

            • cAMP analogue Sp-cAMPS can produce a persistent, slowonset enhancement of synaptic transmission in area CA1 that occludes with tetanus-induced LTP
         3. Kameyama et al., 1998

            Anmerkungen:

            • did not affect basal transmission but reversed LTD, implicating PKA in de-depression
         4. diff mouse strains

            Anmerkungen:

            • strong strain difference in the ability of mice to express cAMP-induced facilitation (Nguyen et al., 2000).
      4. mechanism

         Anmerkungen:

         • These various observations suggest that the role of PKA is probably to modulate, rather than directly mediate, NMDARdependent LTP. One idea is that PKA gates the activity of the pathway leading from activation of CaMKII to the expression of early LTP (Blitzer et al., 1995) via inhibition of the protein phosphatase 1 (PP1), which dephosphorylates CaMKII at ser831 and ser845 (Blitzer et al., 1998). Whether LTP-inducing stimuli induce an increase in the level of cAMP is disputed (Chetkovich and Sweatt, 1993; Blitzer et al., 1995; Pokorska et al., 2003). If there is no increase, constitutive levels of cAMP must be adequate to maintain the gate in its open state.
         1. gateway for CaMKII?
5. Late LTP

   Anmerkungen:

   • hours-days-months

   Anlagen:

   • L-LTP
   1. Protein synthesis
   2. Transcriptional factors
   3. Genomic
   4. Structural changes

      Anlagen:

      • Structural plasticity

Anmerkungen:

• seconds- minures

1. presynaptic
2. transient form of LTP (TLTP)
   1. Volianskis and Jensen, 2003
   2. decays in an activity-dependent manner

      Anmerkungen:

      • 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
3. frequency of afferent stimulation and magnitude of STP- positively correlated

   Anmerkungen:

   • magnitude of STP was influenced by the frequency of afferent stimulation, such that higher frequencies favored larger STP
   1. explains variability in experiments

      Anmerkungen:

      • 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. high-frequency- large STP
      3. low-freq- small STP
4. resistant to kinase inhibitors

   Anmerkungen:

   • with a few exceptions

Anlagen:

• E-LTP- pre or postsynaptic