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| 2. |
- Abbas, Abdul-Karim, 1959, et al.
(författare)
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Persistent LTP without triggered protein synthesis.
- 2009
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Ingår i: Neuroscience research. - : Elsevier BV. - 0168-0102. ; 63:1, s. 59-65
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Tidskriftsartikel (refereegranskat)abstract
- Protein synthesis is believed to be involved in stabilizing synaptic plasticity. Effects lasting longer than about 2-3h are considered to require synthesis of new proteins, implying a functional separation between early (E) and late (L) components. However, the issue of constitutive vs. new protein synthesis is still unclear, especially in young animals. Here, we examined the effects of two protein synthesis inhibitors, anisomycin and emetine, on long-term-potentiation (LTP) in CA1 area of hippocampal slices from 12- to 20-day-old rats. Either drug was applied from -30 min to +30 min with respect to LTP induction, a time window previously reported to be critical. However, the LTP remained stable under the entire recording period of 4h (anisomycin), or 8h (emetine). Proper preparation of emetine solution was evidenced by the fact that, in separate experiments, prolonged treatment with emetine gradually blocked baseline responses. Although no corresponding effect was observed with anisomycin, the drug was judged to be potent by its ability to inhibit yeast growth. The ability of anisomycin to inhibit protein synthesis was further confirmed by radiolabeling experiments assessing the degree of leucine incorporation. Our data suggest that LTP up to at least 8h is not dependent on triggered protein synthesis but can be attained by utilizing proteins already available at induction time.
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| 3. |
- Dozmorov, Mikhail, 1973
(författare)
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Activity-dependent changes of synaptic transmission in a long-term perspective and processes involved
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Synaptic plasticity is an essential property of the central nervous system. It is thought torepresent a mechanism for memory aquisition, storage and recall. The most well studied forms ofsynaptic plasticity are homosynaptic NMDAR-dependent LTP and LTD in the hippocampus inducedby specific patterns of electrical stimulation. The purpose of the present study was to investigate otherpossibilities for induction of synaptic plasticity over prolonged time periods, characterize propertiesand reveal underlying mechanisms of both potentiation and depression.Experiments were performed on hippocampal slices, 400 µm thick, from 12-21 day oldSprague-Dawley rats. Extracellular techniques were used for electrophysiological recording in theapical dendritic layer of pyramidal cells in the CA1 area of the hippocampus. NMDARs wereactivated by using a solution with low Mg2+ concentration (0.1 mM). Either dual or pureAMPA/NMDA receptor mediated EPSPs were monitored.NMDAR activation in low Mg2+ at frequencies used to test synaptic transmission led to aninitial increase and a prolonged decay of either composite or NMDAR mediated EPSPs. This decaywas input specific, saturable, long lasting and required NMDAR activation. In case of dual EPSPs themagnitudes of AMPA and NMDA receptor mediated components followed almost equal time courseand underwent similar amount of decay, reaching about 40% of baseline. Pure NMDAR mediatedEPSPs also decayed substantially, on average down to 60% of peak value. Novel activation ofNMDARs resulted in initial potentiation and subsequent decay of pure NMDAR mediated EPSPs tothe same level as in a continuously stimulated pathway. Interaction experiments suggest that themechanisms underlying the decay are at least partly different from those involved in homosynapticLTP and LTD.The behavior of AMPA/NMDA receptor mediated components was also investigated duringsynaptic potentiation by using a method for dual EPSP assessment during short time intervals( NMDA-sniff ). LTP was induced in different solutions, like low Mg2+ and normal Mg2+ , and bydifferent protocols (HFS, TBS). In all cases the NMDAR mediated EPSP component underwentpotentiation of about half that of the AMPAR mediated component. The ratio between the twocomponents remained stable across early (1 h) and late (4 h) phases of LTP.The possible involvement of protein synthesis in LTP expression was examined by using aprotein synthesis inhibitor anisomycin. No effect of anisomycin on LTP maintenance was observed;however, an overall negative effect of the drug on synaptic transmission was present. The potency ofanisomycin was proved by radiolabelling tests and yeast-growth experiments.These results indicate that NMDARs are important in controlling synaptic plasticity and thattheir weak, prolonged activation leads to decreasing synaptic efficacy. AMPA/NMDA receptormediated components are coupled with each other in terms of their parallel changes during synapticplasticity processes; however, the ratio between changes was different for depression and potentiation.De novo protein synthesis appears not to be an essential factor for LTP maintenance during at least 4 hof its expression. This implies that either the existing amount of proteins is sufficient for LTPmaintenance in young animals or, less likely, that protein synthesis is not required at all.
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| 4. |
- Dozmorov, Mikhail, 1973, et al.
(författare)
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Contribution of AMPA and NMDA receptors to early and late phases of LTP in hippocampal slices.
- 2006
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Ingår i: Neuroscience research. - : Elsevier BV. - 0168-0102. ; 55:2, s. 182-8
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Tidskriftsartikel (refereegranskat)abstract
- Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor mediated responses were investigated in rat hippocampal slices under 4h of long-term potentiation (LTP) expression. A modified medium containing the NMDA receptor antagonist AP5 and low concentration of Mg(2+) was used to monitor isolated AMPA responses. NMDA components were determined from composite excitatory postsynaptic potentials (EPSPs) under brief (15-20 min) wash-out of AP5. LTP was induced in a medium with low concentration of AP5, resulting in an about two-fold larger increase of the AMPA component than of the NMDA component at both 1h and 4h after induction. Similar results were obtained if LTP was induced in "normal Mg(2+)" and the NMDA components were assessed at the end of experiment, from either composite or isolated NMDA EPSPs, with or without blockade of GABAergic inhibition. It is generally believed that LTP undergoes biochemical and/or structural conversions during the first few hours. Our study, however, shows constant expression of LTP, at least in terms of AMPA versus NMDA components, during this time. The data support the notion that LTP initiates as a predominant amplification of AMPA receptors and remains so for at least 4h.
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| 5. |
- Dozmorov, Mikhail, 1973, et al.
(författare)
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Slowly developing depression of N-methyl-D-aspartate receptor mediated responses in young rat hippocampi.
- 2004
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Ingår i: BMC neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Activation of N-methyl-D-aspartate (NMDA) type glutamate receptors is essential in triggering various forms of synaptic plasticity. A critical issue is to what extent such plasticity involves persistent changes of glutamate receptor subtypes and many prior studies have suggested a main role for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in mediating the effect. Our previous work in hippocampal slices revealed that, under pharmacological unblocking of NMDA receptors, both AMPA and NMDA receptor mediated responses undergo a slowly developing depression. In the present study we have further addressed this phenomenon, focusing on the contribution via NMDA receptors. Pharmacologically isolated NMDA receptor mediated excitatory postsynaptic potentials (EPSPs) were recorded for two independent synaptic pathways in CA1 area using perfusion with low Mg2+ (0.1 mM) to unblock NMDA receptors. RESULTS: Following unblocking of NMDA receptors, there was a gradual decline of NMDA receptor mediated EPSPs for 2-3 hours towards a stable level of ca. 60-70 % of the maximal size. If such an experimental session was repeated twice in the same pathway with a period of NMDA receptor blockade in between, the depression attained in the first session was still evident in the second one and no further decay occurred. The persistency of the depression was also validated by comparison between pathways. It was found that the responses of a control pathway, unstimulated in the first session of receptor unblocking, behaved as novel responses when tested in association with the depressed pathway under the second session. In similar experiments, but with AP5 present during the first session, there was no subsequent difference between NMDA EPSPs. CONCLUSIONS: Our findings show that merely evoking NMDA receptor mediated responses results in a depression which is input specific, induced via NMDA receptor activation, and is maintained for several hours through periods of receptor blockade. The similarity to key features of long-term depression and long-term potentiation suggests a possible relation to these phenomena. Additionally, a short term potentiation and decay (<5 min) were observed during sudden start of NMDA receptor activation supporting the idea that NMDA receptor mediated responses are highly plastic.
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| 6. |
- Li, Rui, 1975, et al.
(författare)
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Characterization of NMDA induced depression in rat hippocampus: involvement of AMPA and NMDA receptors.
- 2004
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Ingår i: Neuroscience letters. - : Elsevier BV. - 0304-3940. ; 357:2, s. 87-90
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Tidskriftsartikel (refereegranskat)abstract
- The involvement of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) vs. N-methyl-d-aspartate (NMDA) receptor mediated changes in NMDA-induced long-term depression (LTD) was assessed by monitoring isolated AMPA, isolated NMDA and composite field excitatory postsynaptic potentials (EPSP) in the CA1 area of acute rat hippocampal slices. Application of NMDA (20-50 microM) for 3-5 min led to LTD of both AMPA and NMDA receptor mediated EPSPs with near equal changes of the responses. However, AMPA EPSPs displayed a faster initial recovery than NMDA EPSPs. In addition, during the first 15-25 min after NMDA application, there was a superimposed potentiation of the later, but not early, part of AMPA EPSPs, implying a prolongation of waveform. In contrast, the NMDA EPSP waveform remained unaltered throughout the experiments. While it has been maintained that NMDA-induced depression is equivalent to stimulus-induced LTD, our results reveal additional complexity, suggesting a multitude of changes, most likely at the postsynaptic receptor level.
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