Abstract
BackgroundThe 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 Mg2+ conditions as well as long-term potentiation (LTP).ResultsA 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 Mg2+ concentration in the perfusion solution. Applying NVP or Ro/Ife on isolated NMDA-EPSPs recorded in low Mg2+ 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.ConclusionAll 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 Ca2+ 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.
Highlights
The involvement of different NMDA receptor (NMDAR) subunits has been implicated in several forms of synaptic plasticity
In the first set of experiments, we examined the effects of selective antagonists of NR2A and NR2B subunits on NMDA-induced plasticity
Our results showed that long-term depression (LTD) was uneffected by Ro/Ife, but was largely blocked by NVP, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-excitatory postsynaptic potentials (EPSPs) obtained after the induction period amounting to 45 ± 4% (n = 8, p > 0.1) and 93 ± 4% (n = 7, p < 0.001) of baseline level, respectively
Summary
The involvement of different NMDA receptor (NMDAR) subunits has been implicated in several forms of synaptic plasticity. LTD, on the other hand requires activation at a moderate frequency (e.g. 1 Hz, 15 min) or paring presynaptic activation with lower levels of depolarization, leading to a long-lasting decrease in synaptic efficacy [5,6]. Both types of plasticity depend on NMDA receptor (NMDAR) activation as a first step, evidenced by the fact that they are fully blocked when NMDAR antagonists, such as AP5, are present during the induction. Our previous work on NMDA-induced plasticity has demonstrated multiple changes after NMDA application, some of which may be related to LTP/LTD while others may represent different forms of synaptic plasticity [10]
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