Abstract
BackgroundThe contribution of different GluN2 subunits of the N-methyl D-aspartate (NMDA) receptor to the induction of bidirectional hippocampal synaptic plasticity is a controversial topic. As both supporting and refuting evidence for the hypothesis of subunit specialization in opposing directions of plasticity has accumulated since it was first proposed a few years ago, we hypothesize that differences in experimental conditions may have in part contributed to some of the inconsistent results from these studies. Here we investigate the controversial hypothesis that long-term depression (LTD) is preferentially induced by GluN2B-containing NMDA receptors in area CA1 of hippocampal slices.ResultsWe find that brain slices from 2-3 week old rats prepared in the sagittal orientation have GluN2B-independent LTD whereas slices prepared in the coronal orientation have GluN2B-dependent LTD. There was no difference between the orientations in the fraction of the NMDAR EPSC sensitive to a GluN2B-selective antagonist, leading us to believe that the intracellular signaling properties of the NMDARs were different in the two preparations. Coronal slices had greater association of LTD-related intracellular signaling protein RasGRF1 with GluN2B relative to sagittal slices. Antagonism of muscarinic acetylcholine receptors (mAChRs) in the sagittal slices returned LTD to a GluN2B-dependent form and increased the association of GluN2B with RasGRF1.ConclusionsThese results suggest a novel form of NMDAR modulation by mAChRs and clarify some disagreement in the literature.
Highlights
The contribution of different GluN2 subunits of the N-methyl D-aspartate (NMDA) receptor to the induction of bidirectional hippocampal synaptic plasticity is a controversial topic
Slice orientation determines the involvement of GluN2B in long-term depression (LTD) induction Faced with an apparent contradiction between the results of some groups regarding the involvement of GluN2B in LTD induction, we sought a resolution to the disagreement and an understanding of the underlying physiological mechanism
We found no significant difference between the effect of Ro on the N-methyl D-aspartate receptors (NMDARs) EPSC from CA1 pyramidal cells in slices prepared in the sagittal orientation versus cells from coronal slices (Figure 2, sagittal, n = 8, 39.9 ± 4.72% baseline, Coronal, n = 7, 30.4 ± 5.33% baseline, P = 0.202)
Summary
The contribution of different GluN2 subunits of the N-methyl D-aspartate (NMDA) receptor to the induction of bidirectional hippocampal synaptic plasticity is a controversial topic As both supporting and refuting evidence for the hypothesis of subunit specialization in opposing directions of plasticity has accumulated since it was first proposed a few years ago, we hypothesize that differences in experimental conditions may have in part contributed to some of the inconsistent results from these studies. Based on the prolonged Ca2+ flux requirements for LTD induction [6] and the developmentally decaying profile of artificially inducible LTD [7] matching the early postnatal predominance of GluN2B expression [8], it was hypothesized that GluN2B is important for LTD induction. Outside CA1 the situation is even more complex, with reports that GluN2B is essential for LTD in the perirhinal cortex [10], and that both GluN2A and GluN2B are required for LTD in the amygdala [18] and anterior cingulate cortex [19]
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