Induction of LTP

Adjunto:

• Modulation of LTP

1. Endogenous modulatorrs
   1. Ach
   2. NA
   3. DA
   4. 5-HT
   5. Cannabinoids
   6. glutamate/ GABA
   7. Corticosteriods
2. Glial cells
3. Other

   Nota:

   • Pregnance Smoking Stress Sleep Alzheimers Alcohol Exercise Schizo Gender Cannabis Depression Sex Autisim
   1. STRESS
      1. NA
      2. Corticosteriods

1. Induction protocols

   Adjunto:

   • Techniques in synaptic plasticity
   1. Pairing

      Nota:

      • single stimuli repeated at low frequency are paired with depolarizing pulses that induce brisk firing of the recorded cell
      1. Isaac et al (1995)

         Nota:

         • paired stimulation lead to release of neurotransmitter coupled with depol, which leads to the insertion of receptors in the postsynaptic density
         1. LTP- silent synapses
         2. NMDAR-dependent
      2. Nakamura et al (2011)

         Nota:

         • dependent on the Ca influx
         1. LTD
      3. Wigström et al., 1986

         Nota:

         • demonstrated that low-frequency stimuli could induce LTP in single CA1 pyramidal cells if each stimulus was given in conjunction with a strong depolarizing pulse- association of a presynaptic stimulus with postsynaptic depolarisation
      4. spike timing-dependent potentiation (STDP)

         Nota:

         • the term was introduced by Song et al. (2000)
         1. Bi and Poo, 1998

            Nota:

            • HPC- LTP can be induced by repeated pairing of an afferent stimulus with a single back-propagating action potential, provided the EPSP precedes the action potential by less than ~10 ms
            1. LTP= pre preceds post
            2. LTD- post preceds pre
         2. requires posysynaptic spiking

            Nota:

            • not only does it require tight temporal contiguity of presynaptic and postsynaptic firing, but the back-propagating spike provides the associative signal that informs dendritic synapses that the postsynaptic cell has fired
         3. Backprobagation
            1. Stuart and Sakmann, 1994

               Nota:

               • action potential in cortical pyramidal cells propagates back into the dendritic tree
      5. Abraham et al., 1986; Kelso et al., 1986
      6. activates NMDAR signalling
         1. Collingridge et al., 1988

            Nota:

            • enabled NMDAR-mediated responses to be evoked by single stimuli
         2. Hvalby et al., 1987

            Nota:

            • Pairing single stimuli with iontophoretic application of glutamate was similarly effective at inducing LTP
            1. pairing + glutamate
   2. Theta

      Nota:

      • high-freq stimulation in 5 bursts- similar to show AP occur normally- functionally relevant 
      • theta rhythm (an endogenous hippocamapal rhythm generated during movement)- functionally significant
      1. avies et al., 1991
         1. mechanism
            1. feedforward GABA interneurons

               Nota:

               • The priming stimulus (or initial brief train) activates feedforward GABA interneurons, leading to GABAA- and GABAB- mediated hyperpolarization in the pyramidal cell but, importantly, also to activation of presynaptic GABAB autoreceptors
               1. GABA(B) autoreceptors

                  Nota:

                  • produce a transient reduction in GABA release that is maximal at around 100 to 200 ms. Thus the second train produces much less GABA-mediated hyperpolarization with consequent enhancement of the voltage-dependent NMDA receptor-mediated current
      2. occur naturally

         Nota:

         • Minimal patterns of stimulation of this kind are far more likely to occur naturally than the longer trains of tens or hundreds of stimuli (e.g., 100 Hz for 1 second) that are frequently used for reasons of convenience and custom.
      3. Hyman et al (2003)

         Nota:

         • when TBS was applied at the trough of theta EEG- LTD at the peak- LTP
      4. Lever et al (2010)

         Nota:

         • investigated theta phase of firing in principal cells in subiculum and CA1 as rats foraged in familiar and novel environments. We found that the preferred theta phase of firing in CA1, but not subiculum, was shifted to a later phase of the theta cycle during environmental novelty. Furthermore, the amount of phase shift elicited by environmental change correlated with the extent of place cell remapping in CA1. Our results support a relationship between theta phase and novelty-induced plasticity in CA1
   3. Tetanic

      Nota:

      • needs a long depol to induce LTP because NMDAR activation is slow- needs to remove Mg block etc
      1. Bliss and Gardner-Medwin (1973)

         Nota:

         • study of LTP in awake rabbits, the stimulus intensity during the tetanus must be sufficiently strong
         1. LTP induced above a certain intensity
      2. McNaughton et al. (1978)

         Nota:

         • gradually increased the intensity of tetanization to reveal that LTP occurred only above what they termed the “cooperativity” threshold. PTP was observed at lower intensities with the response amplitude declining to baseline between successive tetanizations
         1. cooperativity threshold

            Nota:

            • stimulating a few fibres at a weak intensity
         2. (-) cooperativity not the only mechanism for induction
      3. one fibre

         Nota:

         • stimulating one fibre at a strong intensity
      4. Magnitude and during of LTP

         Nota:

         • a function of tetanus intensity
         1. eventual saturation
      5. common- 100 Hz for 1 second
      6. single stimuli of high intensity repeated at 1 Hz in the presence of picrotoxin
   4. primed-burst stimulation (PBS)

      Nota:

      • a brief burst of stimuli 
      1. Davies et al (1991)
      2. occur naturally
   5. Theta vs high frequency
      1. Hernandez et al. (2005)

         Nota:

         • major factor controlling the magnitude of LTP is the number of stimuli in a train rather than the pattern of stimulation
         1. difference in early phase, but not late phase LTP
         2. number of pulses determine long-term LTP
2. Induction properties

   Adjunto:

   • Synaptic plasticity
   1. Coopertivity

      Nota:

      • see synaptic plasticity general
      1. Douglas and Goddard, 1975
   2. Associatvitiy
      1. discovered by
         1. McNaughton et al. (1978)
            1. medial and lateral perforant path projections to the ipsilateral dentate gyrus

               Nota:

               • they found that when weak tetani were given simultaneously to the medial and lateral branches of the perforant path, LTP was induced in both pathways, though each tetanus, when given separately, was below the cooperativity threshold
         2. Levy and Steward (1979)
            1. weak- entorhinal-contralateral DG

               Nota:

               • perforant pathway- weak projection
               1. Tetanic stimulation

                  Nota:

                  • incapable of inducing LTP when given alone; but if given at the same time as a tetanus to the strong ipsilateral perforant pathway, LTP was induced in both ipsilateral and contralateral pathways
            2. strong-ipsilateral
      2. Extracellular experiments
         1. DG- Levy and Steward, 1983
         2. CA1- Gustafsson and Wigström, 1986
            1. one “weak” and one “strong” input

               Nota:

               • using a two-pathway protocol with one “weak” and one “strong” input also showed that associative potentiation of the weak pathway requires near-coincidence of weak and strong inputs, with potentiation occurring if the weak immediately precedes the strong input but not if the strong precedes the weak input
      3. function- memory

         Nota:

         • Because of its potential for strengthening co-active inputs, the property of associativity lies at the heart of the role that LTP is likely to play in memory functions of the hippocampus
   3. input-specific
      1. Andersen et al., 1977; Lynch et al., 1977

         Nota:

         • first obtained in area CA1 of the hippocampal slice in experiments using two stimulating electrodes positioned to activate two sets of fibers converging on the same cell population
      2. in neighboring synapses
         1. Haley et al. (1996)

            Nota:

            • suggest that synapse specificity breaks down within a radius of a few tens of microns of a site of potentiation, regardless of whether synapses are on the same target cell or are active at the time of potentiation.
   4. Hebbian plasticity

      Nota:

      • Note that cooperativity, associativity, and input specificity can all be explained on the assumption that the induction of LTP at a given synapse requires presynaptic activity with coincident activation of the postsynaptic neuron. This is very close to the criterion that Hebb proposed for the enhancement of synaptic strength in hypothetical neural circuits mediating associative conditioning (Hebb, 1949).
3. Hebbian induction rule

   Nota:

   • requires a tight coincidence of presynaptic and postsynaptic activity- A synapse will be potentiated if, and only if, it is active at a time when its dendritic spine is sufficiently depolarized
   1. Molecular mechanisms
      1. Ca2+ hypothesis
         1. Rise in Ca is required
            1. Lynch et al., 1983
               1. Ca chelator EGTA

                  Nota:

                  • into CA1 pyramidal cells blocks the induction of LTP using Intracellular recordings- intracellular electrode contained Ca buffer EGTA
            2. Malenka et al. (1992)
               1. caged Caused

                  Nota:

                  • used a caged form of the calcium chelator BAPTA, from which Ca can be rapidly released by a flash of ultraviolet light >>to establish that the obligatory rise in calcium is confined to a window of less than 2.0 to 2.5 seconds following the tetanus.
                  1. Ca rise- 2s following tetanus
            3. Zalutsky and Nicoll (1990)
               1. Ca chealtor blocks LTP induction
         2. mechanism of Ca rise?

            Nota:

            • The mechanisms of Ca could also be not NMDAR mediated, but activated by different mechanisms
            1. Ca release from intracellular stores
               1. Harvey and Collingridge, 1992
                  1. CA1- block refill of store- block induction

                     Nota:

                     • thapsigargin, which prevents the refilling of these stores, can block the induction but not the expression of LTP at CA1 synapses
               2. Ca-induced Ca release

                  Nota:

                  • these data suggest that Ca2-induced Ca2 release can greatly augment the Ca2 signal that permeates NMDA receptors and may be involved in the induction of LTP.
                  1. Obenaus et al., 1989
                     1. ryanodine receptor inhibitor, blocks induction of LTP

                        Nota:

                        • Ca2 may be released from stores via the generation of inositol trisphosphate (IP3) and/or via Ca2-induced Ca2 release media by IP3 and/or ryanodine receptors
                  2. Alford et al (1993)

                     Nota:

                     • tetanic stimulation was shown to elicit a large NMDA receptordependent Ca2 signal at synapses that was substantially inhibited by either thapsigargin or ryanodine
               3. Other?- not studied

                  Nota:

                  • Ca2 release from intracellular stores may be induced by other mechanisms, for example  via activation of voltage-gated Ca2 channels, phospholipase C (PLC)-coupled receptors, or otherCa2-permeable ligand-gated channels. Any of these pathscould, in theory, induce NMDAR-dependent LTP without activating the normal induction trigger, the NMDA receptor itself.
            2. Ca entry via VGCCs

               Nota:

               • enables NMDAR independent LTP voltage-gated Ca channels (VGCCs)
               1. Difficult to test

                  Nota:

                  • 1. using a voltage clamp experiments which clamps only voltage-gated Ca channels, but a perfect clamp of synapses located on dendritic spines is not achievable. 2. pharmacological block of VGCCs is also problematic as certain types are required for neurotransmitter release
                  1. activate VGCC via depol

                     Nota:

                     • activate VGCCs by intracellular depolarization, in the absence of evoked  synaptic transmission
                     1. Wyllie and Nicoll, 1994

                        Nota:

                        • This generally does not induce LTP unless phosphatases are also blocked
               2. may be important, but not necessary

                  Nota:

                  • It is possible that Ca entry via VGCCs could trigger LTP if there is sufficient influx in Ca, however in synapses a sufficient influx is unlikely to occur without the simultaneous activation of NMDAR
               3. Grover and Teyler, 1990).

                  Nota:

                  • higher frequencies during tetanization (e.g., 200 Hz) promote NMDAR-independent LTP in the Schaffer-commissural pathway But this is not necessarily a VGCCs induced, could be other mechanisms
            3. L-type Ca channels
               1. Cav1.2 mutant mice

                  Nota:

                  • mice mutant inactivation of this isoform do not display NMDA receptor-independent LTP
      2. Receptors
         1. NMDAR
            1. Evidence for its role in induction of LTP
               1. genetically engineered mice
                  1. Tsien et al. (1996)
                     1. cre-lox
                     2. NMDAR1 deletion- blocked induction

                        Nota:

                        • a deletion of NMDAR1 (the obligatory subunit of the NMDA receptor) in area CA1 but not in the dentate gyrus. Slices from these animals showed no LTP in CA1 but normal LTP in the dentate gyrus
                  2. Sprengel et al. (1998)
                     1. C-terminal of NR2 subunit deleted

                        Nota:

                        • gene-targeted deletion of NMDAR subunit in mice >> still able to pass Ca currents
                        1. blocked LTP induction

                           Nota:

                           • The inability of these mutants to display LTP despite unaltered Ca2 current through the mutant receptor indicates that the NMDA receptor plays a further role in the genesis of LTP, downstream of its function as a Ca2-permeable ionophore. Transcriptional/ translational mechanisms
                        2. Ca current unaltered
               2. APV blocks LTP induction
                  1. Collingridge et al., 1983

                     Nota:

                     • specific NMDA receptor antagonist APV blocked the induction in CA1 HPC, while having little or no effect on synaptic
                     1. first evidence
                  2. Lynch et al., 1983

                     Nota:

                     • HPC- LTP induction is blocked using AP5 -but has no effect on pre-established LTP
               3. dual ligand and voltage dependence

                  Nota:

                  • offers an elegant molecular mechanism for both the induction of LTP (Collingridge, 1985) and the properties of associativity and input specificity (Wigström and Gustafsson, 1985).q
                  1. conditions for activation:

                     Nota:

                     • presynaptic activity to release glutamate and strong postsynaptic depolarization to relieve the Mg2 block of the NMDA receptor channel
                     1. presynaptic glutamate
                        1. Ca is the trigger

                           Nota:

                           • Because Ca2 is required for the induction of LTP (Lynch et al., 1983), and because activated NMDA receptor channels, unlike most ionotropic AMPA receptor channels, are highly permeable to calcium (MacDermott et al., 1986; Jahr and Stevens, 1987, 1993), it seems reasonable to conclude that the trigger for the induction of LTP is the entry of calcium ions through the channel associated with the NMDA receptor.
                           1. See evidence for the role of Ca
                     2. postsynaptic depol
                        1. Ca is the trigger
            2. characteristics
               1. Ca permeable
               2. blocked by Mg

                  Nota:

                  • at resting levels
               3. voltage-dependent

                  Nota:

                  • which relies on the unblocking of Mg2+
            3. necessary for induction, but not sufficient

               Nota:

               • although the evidence suggests that NMDAR activation is necessary for the induction of LTP, it may not always be sufficient Additional presynaptic and postsynaptic mechanisms may be needed for the induction and expression of LTP- for co-trigerring
               1. NMDAR/ glutamate alone

                  Nota:

                  • neither NMDA (Kauer et al., 1988) nor glutamate (Hvalby et al., 1987), when applied alone to hippocampal slices, readily induces long-lasting potentiation
            4. subunits

               Nota:

               • LTP was found to be more sensitive to NR2A/2B selective antagonists, whilst LTD was more sensitive to NR2C/D selective antagonists (Hrabetova et al., 2000).
               • see hippocampus book 10.3.7
         2. GABA receptors

            Nota:

            • Theoretically, many neurotransmitters and neuromodulators could interact with the LTP induction process via an effect on GABA inhibition. For example, it has been shown that endocannabinoids released from pyramidal neurons can depress GABA inhibition, which can result in the facilitation of LTP
            1. Wigström and Gustafsson, 1983

               Nota:

               • blockade of GABA inhibition can greatly facilitate the induction of NMDARdependent LTP
               1. GABA inhibition- facilitates induction of LTP
            2. GABA(A)

               Nota:

               • leads to rapid IPSP
               1. Herron et al., 1985

                  Nota:

                  • When GABAA receptors were blocked pharmacologically, an NMDAR-mediated synaptic response appeared during low-frequency stimulation in the presence of Mg2
            3. GABA(B) autoreceptor

               Nota:

               • a slow mechanism leading to IPSP
               1. priming stimulus
                  1. Davies et al (1991)

                     Nota:

                     • GABA that is released in response to the priming stimulus feeds back to activate GABAB autoreceptors, which results in inhibition of subsequent GABA release. Thus, the priming stimulus releases a normal level of GABA, but the stimuli during the burst release considerably less GABA, which facilitates the synaptic activation of NMDA receptors on pyramidal neurons.
               2. GABA(B) anta

                  Nota:

                  • when applied at concentrations that prevent the GABAB autoreceptor from operating and thereby maintain GABAA receptor-mediated inhibition, completely prevent induction of LTP by priming stimulation
            4. mechanism

               Nota:

               • Normally, when an EPSP is evoked by stimulation of an afferent pathway, such as the Schaffer commissural projection, it is curtailed by a biphasic inhibitory postsynaptic potential (IPSP) comprising a rapid GABAA receptor-mediated component and a slower GABAB receptor-mediated component. The hyperpolarizing effect of the IPSP intensifies the Mg2 block of NMDARs, and this greatly limits the extent to which NMDARs contribute to the synaptic response.
         3. mGluRs

            Nota:

            • metabotropic glutamate receptors
            1. mGluR anta- MCPG
               1. +

                  Nota:

                  • MCPG blocked induction of LTP
                  1. Bashir et al., 1993

                     Nota:

                     • MCPG had no effect on basal synaptic transmission or the expression of LTP but completely inhibited the induction of LTP in a fully reversible manner
                     1. block induction, not expression or STP
                  2. Riedel and Reymann, 1993; Sergueeva et al., 1993; Richter-Levin et al., 1994
               2. -

                  Nota:

                  • MCPG didnt block induction of LTP
                  1. Manzoni et al., 1994; Selig et al., 1995b; Thomas and O’Dell, 1995; Martin and Morris, 1997
               3. Explanation for controversy

                  Nota:

                  • MCPG-sensitive mGluRs may be necessary for the induction of LTP under certain, but not all, experimental conditions.
                  1. Bortolotto et al., 1994

                     Nota:

                     • activation of mGluRs did not have to occur at the same time as the tetanus that activated NMDA receptors
                     1. molecular switch?

                        Nota:

                        • Thus, the induction of LTP in one pathway prevented MCPG from inhibiting the induction of more LTP in the same pathway. The initial conditioning tetanus did not have to induce LTP, as a tetanus delivered in the presence of an NMDAR antagonist still produced the conditioning. This led to the proposal that the activation of mGluRs sets a “molecular switch” that negates the need for subsequent activation of mGluRs for induction of LTP in that pathway. Once activated, the switch remains set for at least several hours unless it is turned off by a depotentiating stimulus
                        1. metaplasticity
                        2. if mGluR was activated in the past, it will remain active for a period of time
            2. mGluR agonist- ACPD
               1. Bortolotto and Collingridge, 1993
                  1. induce LTP without the STP phase

                     Nota:

                     • A slow onset of potentiation
                  2. slow onset of potentiation not prevented by NMDAR anta

                     Nota:

                     • but it occluded NMDAR-dependent tetanus-induced LTP, suggesting convergence with the mechanisms underlying the expression of classical LTP
            3. mechanism
               1. release Ca from stores

                  Nota:

                  • Theory- Group I mGluRs (mGluR1 and mGluR5) couple to phospholipase C, leading to the liberation of IP3, which acts on IP3 receptors to trigger Ca2 release from intracellular stores
                  • Theory- ACPD excites CA3 pyramidal cells sufficiently to depolarize CA1 neurons, which in turn may lead to the sensitization of intracellular Ca2 stores to the mGluR-triggered generation of IP3
                  1. CA1- Bortolotto and Collingridge, 1995
                     1. ACPD and MCPG- activate and inhibit mGluR1 and 5
                  2. Rae et al., 2000

                     Nota:

                     • depolarization of CA1 neurons greatly facilitates the Ca2- mobilizing response to group I mGluR agonists
            4. knockouts
               1. knockout mGluR1

                  Nota:

                  • was reported either to inhibit (Aiba et al., 1994) or to have no effect (Conquet et al., 1994) on the induction of LTP
               2. mGluR7 knockout

                  Nota:

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

               Nota:

               • LY341495, a compound that can be used at high concentrations to block all known mGluRs (mGluR1-8), had no effect on LTP (Fitzjohn et al., 1998).
               • The difference between the effects of MCPG and LY341495, which can demonstrated in the same pathway, suggests that either MCPG is acting on some receptor other than mGlu1-8 or that the blanket inhibition of mGluRs has effects that are different from the selective inhibition of some subunits
      3. CaMKII

         Nota:

         • 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). CaMKII inhibitors have no effect on theinduction of LTP

         Adjunto:

         • Expression of LTP

1. Onset
   1. (-) hard to determine because of PTP

      Nota:

      • because it is confounded by the extremely rapid onset of PTP
      1. study PTP in isolation

         Nota:

         • using trains subthreshold for LTP or in the presence of AP5, which blocks the induction of LTP without affecting PTP, and by making the assumption that LTP and PTP are independent processes, it is possible to dissect out the two processes
         1. trains subthreshold for LTP
         2. AP5- blocks LTP without affecting PTP
   2. CA1
      1. Hanse and Gustafsson, 1992
         1. begins within 2-3s
         2. peaks- 30s
         3. declines to a more stable value- 10-20min
   3. DG
      1. Hanse and Gustafsson, 1992
         1. in-vitro, tetanus induced
         2. peaks- 1-2min
         3. (-) confounded by stimulus protocol

            Nota:

            • Estimates are confounded, however, by the possibility that onset kinetics are modulated by the test stimuli given to sample synaptic responses
2. How long it lasts depends on:
   1. stimulation protocol
   2. type of preparation
      1. (-) limited to the lifetime of preparation
      2. intact animals, DG
         1. a few days-years
   3. region of HPC
      1. LTP induction not successful everywhere
         1. stimulation protocol/ damaged preparation

            Nota:

            • However, this may reflect an unhealthy or dialyzed cell or an inappropriate stimulus protocol for that synapse.
         2. Petersen et al. (1998)
            1. 45% -75% of excitatory synapses in area CA1 can be potentiated

               Nota:

               • not all synapses can be potentiated
               1. saturated synapses?

                  Nota:

                  • Unpotentiable connections may represent synapses at which LTP has been saturated and that might therefore be more susceptible to LTD-inducing stimulation, but 63% of nonpotentiable connections in the experiments of Debanne et al. (1999) could not be depressed either
               2. 10% to 20% don't exhibit synaptic plasticity