Contribution of NR2A and NR2B NMDA subunits to bidirectional synaptic plasticity in the hippocampus in vivo

Abstract

It has recently been proposed that activation of the NR2A subunit results in Long-term potentiation (LTP) induction, whereas activation of the NR2B subunit results in long-term depression (LTD) induction. The present study undertakes to replicate these findings in vivo to determine if a role for specific subunits in synaptic plasticity can be shown in the intact brain. Field recordings were made from the CA1 subfield of the hippocampus using Schaffer collateral stimulation in anesthetized male Sprague-Dawley rats. Antagonists of the N-methyl-D-aspartate receptors NR2A and NR2B subunits were administered by either intraperitoneal (i.p.) or intrahippocampal (i.h.) injections to assess their involvement in LTP (100 Hz stimuli) and LTD (200 Paired-burst stimuli). i.h. injection of Ro25-6981 (100 microM) significantly attenuated hippocampal LTP expression and completely blocked LTD expression. When administered i.p., Ro25-6981 (6 mg/kg) again blocked LTD, but did not significantly diminish the expression of LTP. When NVP-AAM077 was administered i.h. (80 microM) both LTP and LTD were completely abolished. The administration of this compound i.p. (1.2 mg/kg) also significantly attenuated LTP, but did not affect LTD. These data suggest that both NR2A and NR2B subunits can play roles in LTP and LTD in the hippocampus in vivo.

Disruption of AMPA Receptor Endocytosis Impairs the Extinction, but not Acquisition of Learned Fear

“…Of particular relevance to the present argument is the fact that NMDA NR2B receptor activation is required for the induction of LTD in vitro under some circumstances Liu et al, 2004;Woo et al, 2005;Izumi et al, 2006; but see Hendricson et al, 2002;Morishita et al, 2007) and for NMDA-induced AMPA receptor endocytosis in cultured neurons (Kim et al, 2001;Tigaret et al, 2006). Indeed, recent studies have demonstrated that systemic administration of Ro 25-6981 at the same dose used in the present study blocked selectively the induction of LTD while having no effect on LTP in the hippocampus in vivo (Fox et al, 2006;Wong et al, 2007). The Tat-GluR2 3Y peptide used in these experiments has also been shown to block the expression of LTD specifically through the blockade of regulated AMPA receptor endocytosis (Ahmadian et al, 2004;Brebner et al, 2005;Fox et al, 2007).…”

“…Nevertheless, the studies discussed above strongly suggest that the lateral nuclei of the amygdala may be an important neuroanatomical locus where blockade of AMPA receptor endocytosis or NMDA NR2B receptors would affect this form of learning. However, it is equally plausible that these effects may be due to alterations in synaptic mechanisms in the hippocampus, given that (1) both Tat-GluR2 3Y and Ro 25-6981 disrupt LTD formation in the hippocampus (Fox et al, 2006(Fox et al, , 2007Duffy et al, 2007) and (2) inactivation of this region causes a similar impairment in extinction learning (Corcoran et al, 2005). The effects of local administration of these drugs in the hippocampus and amygdala on fear extinction are the topic of current investigation in our laboratory.…”

“…Dose and route of administration for Tat-GluR2 3Y and Tat-GluR2 3S were chosen with reference to Brebner et al (2005). Dose and route of administration of Ro 25-6981 was chosen with reference to Fox et al (2006). Previous studies from our laboratory (Brebner et al, 2005) have shown that the same dose (1.5 mmol/kg) of fluorescently tagged Tat-GluR2 3Y reaches peak concentrations in the brain 90 min after an i.v.…”

“…In light of emerging evidence that LTD-and NMDAinduced AMPA receptor endocytosis can also be selectively disrupted by NMDA NR2B receptor subunit-selective antagonists (Kim et al, 2001;Liu et al, 2004;Fox et al, 2006;Tigaret et al, 2006;Duffy et al, 2007;Wong et al, 2007), we used the selective NMDA NR2B receptor subunit antagonist Ro 25-6981 as a positive control for assessing the behavioral effects of LTD blockade. As such, the aim of Experiment 3 was to replicate the effects of the Tat-GluR2 3Y peptide on fear extinction using the selective NMDA NR2B antagonist Ro 25-6981.…”

Hippocampal long-term depression is required for the consolidation of spatial memory

“…For example, the GluN2A preferential antagonist NVP-AAM077 (NVP) (19) and the GluN2B-specific antagonist Ro25-6981 (Ro) (20) selectively inhibit LTP and LTD, respectively, in anesthetized rats (18,21). If such GluN2 subunitselective requirements for LTP and LTD can be shown in freely moving animals, these subunit-preferential antagonists may be useful in delineating the roles of LTP and LTD in spatial memory.…”