Critical and complex role of N-methyl-D-aspartate receptors in long-term depression at CA3-CA1 synapses in the developing hippocampus.

In the developing brain synaptogenesis is accompanied by elimination of synapses possibly initiated by activity-dependent synaptic plasticity such as long-term depression (LTD). Experiments using 2nd postnatal week hippocampal CA3-CA1 synapses have previously shown that these synapses, in contrast to those in the more adult brain, are easily depressed even during very low frequency (0.05-0.2 Hz) activity. We have now addressed the question whether such stimulation actually results in LTD, and if so, under which conditions this occurs. By introducing 30-60 min of stimulus interruption following 900 stimuli at 0.2 Hz and 0.05 Hz we found this stimulation to result in an LTD of -37% and -24%, respectively. The LTD following 0.2 Hz stimulation did not differ significantly from that resulting from 900 stimuli using the common LTD-inducing frequency of 1 Hz. When 0.2 Hz and 1 Hz stimulations were applied in the presence of a combined N-methyl-d-aspartate receptor (NMDAR)/mGluR blockade the LTDs were only marginally smaller. However, the LTD observed under this latter condition was labile in that it reversed (de-depressed) by spontaneous and/or ambient NMDAR activity (labile LTD). 0.2 and 1 Hz-evoked NMDAR activity resulted in LTD not de-depressed by spontaneous and/or ambient NMDAR activity (stable LTD) and in little or no labile LTD. The stable LTD was fully de-depressed by high frequency-evoked NMDAR activity. 0.2 and 1 Hz-evoked mGluR activity impaired the labile LTD but did not result in stable LTD. In conclusion, in 2nd postnatal week CA3-CA1 synapses LTD is induced at frequencies well below one Hz as well as in the absence of NMDAR activity. Very low/low frequency-evoked NMDAR activity stabilizes LTD by raising its threshold for NMDAR-dependent de-depression. LTD at these developing synapses thus seems adapted for ease of induction as well as of de-depression.