Activation of NR2B-containing NMDA receptors is not required for NMDA receptor-dependent long-term depression
Introduction
Although the phenomena of long-term potentiation (LTP) and long-term depression (LTD) have been studied for well over 15 years, much remains unknown about the detailed mechanisms responsible for their triggering and expression. In the CA1 region of the hippocampus, it is well accepted that the triggering of the prototypic forms of LTP and LTD requires activation of postsynaptic NMDA receptors (NMDARs) and the consequent rise in intracellular calcium concentration (Malenka and Bear, 2004, Malenka and Nicoll, 1993). Several lines of evidence suggest that the degree of NMDAR activation and as a consequence, quantitative differences in the magnitude and perhaps time course of the postsynaptic calcium elevation dictate whether LTP or LTD is elicited (Bear and Malenka, 1994, Cummings et al., 1996, Malenka and Nicoll, 1993, Yang et al., 1999). Recently, an alternative hypothesis for the triggering of LTP and LTD has been suggested: that the subunit composition of NMDARs dictates whether LTD or LTP is generated (Liu et al., 2004, Massey et al., 2004). Specifically, it has been proposed that activation of NR2B-containing NMDARs leads to LTD whereas activation of NR2A-containing NMDARs leads to LTP. The evidence in support of this hypothesis primarily comes from pharmacological experiments. Selective antagonists of NR2B-containing NMDARs were reported to block LTD, but not LTP, in the CA1 region of the hippocampus (Liu et al., 2004) and the perirhinal cortex (Massey et al., 2004) while antagonists of NR2A-containing NMDARs had the opposite effects, blocking LTP but not LTD.
Several findings that involve molecular manipulations are difficult to reconcile with this NMDAR subunit specificity of LTP and LTD induction. Overexpression of NR2B led to enhanced LTP in the hippocampus (Tang et al., 1999) and activation of NR2B-containing NMDARs could generate LTP in mice lacking NR2A (Kiyama et al., 1998, Weitlauf et al., 2005) or with impaired NR2A-mediated signaling (Kohr et al., 2003). The ability of NR2B-containing NMDARs to trigger LTP could be attributed to compensatory mechanisms caused by the prolonged molecular manipulations. More recently, however, the specificity of the drug used to block NR2A-containing NMDARs, NVP-AAM077, has been questioned as has the critical importance of these NMDARs in LTP induction (Berberich et al., 2005, Weitlauf et al., 2005).
Here, three independent groups have examined the LTD component of this hypothesis; that NR2B-containing NMDARs play a critical role in the triggering of LTD. All three groups independently find that in the CA1 region of the hippocampus the well-accepted selective antagonist of NR2B-containing NMDARs, ifenprodil, at concentrations that clearly reduce NMDAR-mediated synaptic responses, has no significant effect on LTD. These results are difficult to reconcile with the hypothesis that NR2B-containing NMDARs play a critical, obligatory role in the triggering of NMDAR-dependent LTD.
Section snippets
Stanford Group
Transverse hippocampal slices (400 μm thick) were prepared from 3–5 week old Sprague–Dawley rats. Slices were cut in ice cold sucrose solution containing (in mM): sucrose 238, KCl 2.5, NaH2PO4 1, NaHCO3 26.2, CaCl2 1, MgSO4 2 and D-glucose 11 (saturated with 95% O2/5% CO2) and transferred to a holding chamber filled with external solution consisting (in mM): NaCl 119, KCl 2.5, NaH2PO4 1, NaHCO3 26.2, CaCl2 2.5, MgSO4 1.3 and D-glucose 11 (saturated with 95% O2/5% CO2). Slices were allowed to
Stanford Group
In previous work, the NR2B antagonists ifenprodil (3 μM) and Ro-25-6981 (0.5 or 3 μM) were found to block LTD in the CA1 region of the hippocampus (Liu et al., 2004) and perirhinal cortex (Massey et al., 2004). Surprisingly, however, we found that exposure of hippocampal slices for prolonged periods (30–120 min) to either of these NR2B antagonists had no detectable effect on the ability to elicit robust LTD when compared to interleaved control slices. In fact, consistent with a previous study (
Discussion
We have presented results from three independent groups that normal LTD can be generated in the CA1 region of the hippocampus in the presence of selective antagonists of NR2B-containing NMDARs. All three groups also examined the effects of the antagonists on NMDAR-mediated synaptic responses and found that the concentrations of antagonists used were sufficient to clearly reduce NMDAR EPSCs. These latter findings provide direct evidence that the antagonists reached synaptic NMDARs at effective
Acknowledgements
This work was supported by grants from the National Institutes of Health to RCM, RAN and MFB.
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These authors contributed equally to this work.