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Activity-dependent changes of synaptic transmission in a long-term perspective and processes involved

Doktorsavhandling
Författare Mikhail Dozmorov
Datum för examination 2005-03-04
ISBN 91-628-6419-X
Publiceringsår 2005
Publicerad vid Institutionen för fysiologi och farmakologi, Avdelningen för medicinsk fysik
Språk en
Ämnesord synaptic plasticity, hippocampus, LTP, LTD, AMPA, NMDA, protein synthesis
Ämneskategorier Medicin och Hälsovetenskap

Sammanfattning

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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