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      Role of NMDA receptor subtypes in different forms of NMDA-dependent synaptic plasticity

      1 , , 1 , 1 , 1
      BMC Neuroscience
      BioMed Central

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          The involvement of different NMDA receptor (NMDAR) subunits has been implicated in several forms of synaptic plasticity. However, it is still controversial to what extent the involvement is specific, and little is known about the role of NMDAR subunits in certain "non-conventional" forms of plasticity. In this study we used subunit-specific blockers to test the roles of NR2A- and NR2B-containing NMDARs in a type of chemical long-term depression (LTD) induced by brief bath application of the NMDAR agonist NMDA to hippocampal slices from 12–18 days old rats. For comparison, we also examined other forms of plasticity, including a "slow LTD" induced by 0.1 Hz stimulation under low Mg 2+ conditions as well as long-term potentiation (LTP).


          A blocker of NR2A-containing NMDARs, NVP-AAM077 (NVP), substantially reduced the two forms of studied depression whereas blockers of NR2B-containing NMDARs, Ro25-6981 (Ro) or Ifenprodil (Ife), had no significant effect on them. LTP appeared to be more sensitive as it was fully blocked by NVP and partially blocked by Ro or Ife. However, the blocking effects of NVP could be counteracted by general amplification of NMDA responses by lowering Mg 2+ concentration in the perfusion solution. Applying NVP or Ro/Ife on isolated NMDA-EPSPs recorded in low Mg 2+ solution reduced responses to about 70% and 20% of initial size, respectively, whereas coapplication of both blockers almost completely abolished the responses. Additionally, NMDA application caused depotentiation of a pathway with prior tetanus-induced LTP, and NVP but not Ro/Ife substantially prevented that depotentiation as well as the chemical LTD of the control pathway. A second tetanus on the LTP pathway induced repotentiation which was fully blocked by NVP but partially blocked by Ro/Ife.


          All of these results on hippocampal slices from young rats can be explained by a simple model, in which NR2A subunits dominate over NR2B subunits with respect to both plasticity and NMDAR-mediated responses. The model suggests that Ca 2+ influx into the postsynaptic spine via different subtypes of NMDARs makes up a "final common pathway", controlling synaptic plasticity by its magnitude and temporal pattern regardless of the source.

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          Most cited references38

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          Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.

          An in situ study of mRNAs encoding NMDA receptor subunits in the developing rat CNS revealed that, at all stages, the NR1 gene is expressed in virtually all neurons, whereas the four NR2 transcripts display distinct expression patterns. NR2B and NR2D mRNAs occur prenatally, whereas NR2A and NR2C mRNAs are first detected near birth. All transcripts except NR2D peak around P20. NR2D mRNA, present mainly in midbrain structures, peaks around P7 and thereafter decreases to adult levels. Postnatally, NR2B and NR2C transcript levels change in opposite directions in the cerebellar internal granule cell layer. In the adult hippocampus, NR2A and NR2B mRNAs are prominent in CA1 and CA3 pyramidal cells, but NR2C and NR2D mRNAs occur in different subsets of interneurons. Recombinant binary NR1-NR2 channels show comparable Ca2+ permeabilities, but marked differences in voltage-dependent Mg2+ block and in offset decay time constants. Thus, the distinct expression profiles and functional properties of NR2 subunits provide a basis for NMDA channel heterogeneity in the brain.
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            Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path.

            1. The after-effects of repetitive stimulation of the perforant path fibres to the dentate area of the hippocampal formation have been examined with extracellular micro-electrodes in rabbits anaesthetized with urethane.2. In fifteen out of eighteen rabbits the population response recorded from granule cells in the dentate area to single perforant path volleys was potentiated for periods ranging from 30 min to 10 hr after one or more conditioning trains at 10-20/sec for 10-15 sec, or 100/sec for 3-4 sec.3. The population response was analysed in terms of three parameters: the amplitude of the population excitatory post-synaptic potential (e.p.s.p.), signalling the depolarization of the granule cells, and the amplitude and latency of the population spike, signalling the discharge of the granule cells.4. All three parameters were potentiated in 29% of the experiments; in other experiments in which long term changes occurred, potentiation was confined to one or two of the three parameters. A reduction in the latency of the population spike was the commonest sign of potentiation, occurring in 57% of all experiments. The amplitude of the population e.p.s.p. was increased in 43%, and of the population spike in 40%, of all experiments.5. During conditioning at 10-20/sec there was massive potentiation of the population spike (;frequency potentiation'). The spike was suppressed during stimulation at 100/sec. Both frequencies produced long-term potentiation.6. The results suggest that two independent mechanisms are responsible for long-lasting potentiation: (a) an increase in the efficiency of synaptic transmission at the perforant path synapses; (b) an increase in the excitability of the granule cell population.
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              Heteromeric NMDA receptors: molecular and functional distinction of subtypes.

              The N-methyl D-aspartate (NMDA) receptor subtype of glutamate-gated ion channels possesses high calcium permeability and unique voltage-dependent sensitivity to magnesium and is modulated by glycine. Molecular cloning identified three complementary DNA species of rat brain, encoding NMDA receptor subunits NMDAR2A (NR2A), NR2B, and NR2C, which are 55 to 70% identical in sequence. These are structurally related, with less than 20% sequence identity, to other excitatory amino acid receptor subunits, including the NMDA receptor subunit NMDAR1 (NR1). Upon expression in cultured cells, the new subunits yielded prominent, typical glutamate- and NMDA-activated currents only when they were in heteromeric configurations with NR1. NR1-NR2A and NR1-NR2C channels differed in gating behavior and magnesium sensitivity. Such heteromeric NMDA receptor subtypes may exist in neurons, since NR1 messenger RNA is synthesized throughout the mature rat brain, while NR2 messenger RNA show a differential distribution.

                Author and article information

                BMC Neurosci
                BMC Neuroscience
                BioMed Central (London )
                26 July 2007
                : 8
                : 55
                [1 ]Department of Medical Biophysics, Institute of Neuroscience and Physiology, Göteborg University, Box 433, 405 30 Göteborg, Sweden
                Copyright © 2007 Li et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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