How long term potentiation ltp works

In other words, there is a typical cascade of biochemical reactions which can have many different effects. As a result, the postsynaptic neuron becomes further depolarized, thus contributing to LTP.

CREB plays a major role in gene transcription, and its activation leads to the creation of new AMPA receptors that can increase synaptic efficiency still further. CaM kinase II can then in turn phosphorylate the AMPA receptors and probably other proteins such as MAP kinases, which are involved in the building of dendrites, or the NMDA receptors themselves, whose calcium conductance would be increased by this phosphorylation. To give some idea of the complexity of the metabolic sequences responsible for LTP, we will mention three of the other enzymes currently being studied.

In addition to all of the post-synaptic mechanisms involved in the establishment of LTP , it has long been postulated that some presynaptic modifications occur during the ensuing maintenance phase.

But certain modifications, such as an increase in the amount of glutamate released by the presynaptic neuron, would imply the presence of a retrograde messenger that goes back to this neuron and modifies it. Because nitric oxide NO is a gas in its natural state, and can thus diffuse through cell membranes, it would be an ideal candidate for this role.

But its involvement is still the subject of much debate and controversy. Funding for this site is provided by readers like you. Chapter Immune System. Chapter Reproduction and Development. Chapter Behavior. Chapter Ecosystems. Chapter Population and Community Ecology. Chapter Biodiversity and Conservation.

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Chapter Plant Structure, Growth, and Nutrition. Chapter Plant Reproduction. Chapter Plant Responses to the Environment. Full Table of Contents. This is a sample clip. Sign in or start your free trial. JoVE Core Biology. Previous Video Next Video. Next Video Embed Share. Long-term potentiation, or LTP, is a process of synaptic strengthening that occurs over time between pre and post synaptic neuronal connections.

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In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. However, the regulatory mechanism of bidirectional plasticity at excitatory synapses remains unclear. NMDA N-methyl-D-aspartate receptor-dependent long-term potentiation LTP and long-term depression LTD of signal transmission in excitatory neurons, such as hippocampal pyramidal neurons, is thought to underlie the formation of neuronal circuits during learning and memory 1 , 2 , 3.

AMPAR trafficking model at hippocampal postsynaptic neurons. The AKAP signaling complex forms the dimer as shown in b though, for simplification, not shown in d — e. In the present study, we build a network model to reproduce NMDA-receptor dependent bidirectional synaptic plasticity of hippocampal neurons.

All of the molecular mechanisms incorporated into the model work downstream of these CaMKII functions; thus, the normal activities of CaMKII are necessary and implicitly assumed in our network model. Recently, Penn et al. Therefore, the diffusion dynamics on the membrane strongly affect the form of LTP expression and play a crucial role in the rapid short-range diffusion relocation of AMPARs from the peri-synaptic to the synaptic membrane. It was also demonstrated by the duration of STP 26 that the short-range diffusion relocation takes, at most, only 2 min.

Alternatively, that observation does not necessarily exclude the short-range diffusional relocation pathway from the promising AMPAR recruitment pathway during LTP. This hypothesis suggests that the total amount of AMPARs exocytosed at the peri-synaptic membranes should be sufficiently greater than that at the synaptic membrane due to the larger area of peri-synaptic membranes.

In general, the normal lateral diffusion process is isotropic; thus, the flux of lateral diffusion from a place in the extrasynaptic region toward the synaptic membrane and from this place in the opposing direction are in equilibrium for instance Therefore, the cell surface lateral diffusion movement is thought to be ineffective for long-range directional transport of AMPARs.

The long-range transport of AMPARs should necessitate directional non-equilibrium active movement, e. In the network model presented here, we incorporate elemental processes involved in AMPAR trafficking cycles that have been characterized experimentally for hippocampal postsynaptic neurons Fig. We explicitly take into consideration the active transport of recycling endosomes containing AMPARs by myosin V b in our network model.

The exocytic AMPARs incorporated into the peri-synaptic membrane are relocated into the synaptic membrane via a local diffusional movement, which takes, at most, only 2 min, as shown by the observation on the duration of STP In the present study, we did not introduce enough fine space resolution into our network model to identify whether AMPARs are located at the peri-synaptic or synaptic membrane.

This insertion mechanism resolves the long-standing contradiction between the prompt LTP induction and the several-minute delay on the starting time of myosin V b transport following LTP This network model is based on the experimental observations that are summarized in Fig.

The lateral diffusion relocation of AMPAR is assumed to occur during the phosphorylation and dephosphorylation of AMPAR at the synaptic membrane, in addition to the local diffusional relocation movement of the exocytic AMPAR from the peri-synaptic to synaptic membrane. The ordinary differential equations for the network model comprised of reaction equations on components were solved using COPASI biochemical system simulator ver.

The detailed description of the model including components, reactions, and parameters can be found in the SI text. We employed the steady-state concentrations as the initial condition and performed the simulations of the LTP and LTD inductions for 5, s.

These results indicate the validity of the network model for bidirectional synaptic plasticity. Here, it is noted that the network model reproduces the slow reduction in the amplitude of LTP and LTD toward the basal condition, which has been observed experimentally. Here and hereafter, we use square brackets to refer to concentrations. As a result, the PICK1-mediated endocytosis overcomes the Syt1-mediated exocytosis, causing the induction of LTD the numerical results will be provided below.

It has been reported that the regulatory mechanism of AMPAR trafficking on hippocampal synaptic plasticity of rodents is development dependent. Thus, the regulatory mechanism of hippocampal bidirectional synaptic plasticity presented in this study is valid, especially for adult rodents. On the other hand, the endocytic flux should be much larger than the exocytic flux during LTD stimulation Fig.

Nevertheless, LTD is induced by a smaller endocytic flux than during LTP stimulation because during LTD, the exocytic flux is sufficiently smaller than the endocytic flux. Likewise, LTP is induced even though the endocytic flux is larger than that following LTD stimulation because during LTP stimulation the exocytic flux is sufficiently higher than the endocytic flux.

S4 are the convincing evidence that supports our competition mechanism of bidirectional synaptic plasticity. The long-term flux by myosin V b transport is found in Fig. The result obtained for LTP is consistent with experimental observations where the cooperative movements of recycling endosomes and myosin V b molecules start a few minutes later than the LTP induction, and continue for several minutes Thus, the recycling endosomes in the cytosol are constitutively transported by myosin V b toward the peri-synaptic and synaptic membranes.

Consequently, the recycling endosomes are expected to become localized on the membrane surface under basal conditions. Such localization is necessary for the immediate exocytosis mediated by Syt1 after LTP stimulation.

Simultaneously, the AMPAR population at the membranes increases due to Syt1-mediated exocytosis, then immediately begins to decrease after it reaches its peak see Fig. Likewise, endocytic vesicles internalized during LTD induction are also transported by myosin V b and are present in greater quantities on the membrane surface than under basal conditions Fig.

The former is useful to reveal how myosin V b transport affects LTP induction. Indeed, on the basis of localization of AMPARs at the synaptic membrane regulated by phosphorylation of GluA1 S, a model of bidirectional synaptic plasticity has been proposed Our network model reproduces the experimentally observed reduction in LTP due to the inhibition of myosin V b transport Fig. Additional demonstrations of the network model are presented in Supplementary Fig.

These simulation results are also useful to further support the validity of the bidirectional regulatory mechanism of the network model on the induction of both LTP and LTD. Myosin V b transport predominantly governs the long-term behavior of LTP induction. It is noted that R1R2 pS 2 -PICK1 shown in c is not displayed in d because it is present at levels lower than the other components shown here.

Whilst the increase in the normalized endocytic flux is unexpected, it can be interpreted through changes in the population that are related to PICK1-bound species, to which myosin V b does not directly bind Supplementary Fig. In fact, the cooperative movement of recycling endosomes and myosin V b molecules starts several minutes later than LTP induction. On the other hand, the accelerated reduction in LTP magnitude toward basal levels compared with the wild-type model can be interpreted as the direct effects due to inhibition of myosin V b transport.

In Fig. Myosin V b is widely expressed in most neurons, including those in the hippocampus, which implies the possibility that myosin V b could mediate endosomal trafficking during LTP induction 40 , 42 , These facts, that seem to contradict each other at first glance, are actually not problematic, at least in the context of hippocampal LTP.

In our simulation, the flux from myosin V b transport of newly internalized endosomes reaches a maximum at 2 min after the onset of LTP stimulation Fig. Even so, LTP induction can still be reproduced by the network model. Therefore, the short-range diffusional relocation pathway of exocytic AMPAR from the peri-synaptic membranes should be more dominant than the direct exocytosis pathway of AMPAR into the synaptic membrane.

Schematic model of a hippocampal postsynaptic membrane. The graph shows the time courses of the total concentrations for cytoplasmic components, namely, pre-exocytic recycling endosomes that are localized on the membrane surface and newly internalized endosomes, during LTP induction. The pre-exocytic recycling endosomes are steeply decreased by Syt1-mediated exocytosis, then are gradually increased by the myosin-V b active transport of newly internalized recycling endosomes by PICK1-mediated endocytosis.

Whitlock, J. Learning induces long-term potentiation in the hippocampus. Science , — Kemp, A. Hippocampal long-term depression: master or minion in declarative memory processes?. Trends Neurosci. Ge, Y. Hippocampal long-term depression is required for the consolidation of spatial memory. Lu, W. Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach.

Neuron 62 , — Cold Spring Harb. Chater, T. The role of AMPA receptors in postsynaptic mechanisms of synaptic plasticity. Granger, A. Expression mechanisms underlying long-term potentiation: a postsynaptic view, 10 years on. B Biol. Park, M.