Activation of extrasynaptic NMDA receptors induces LTD in rat hippocampal CA1 neurons

In the adult rat hippocampus, activation of N-methyl-d-aspartate receptors (NMDARs) is required for the induction of certain forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). Several studies have indicated the opposing role of synaptic NMDARS (S-NMDARs) versus extrasynaptic NMDARs (ES-NMDARs) in CREB-dependent gene regulation and neuronal survival/death. The contribution of ES-NMDARs in synaptic plasticity, however, remains unclear. Here we investigated the contribution of ES-NMDARs on LTD induction in CA1 neurons of rat hippocampal slices. ES-NMDARs were selectively activated by theta burst stimulation (TBS) after selective blockade of S-NMDARs with pairing of 5 Hz stimulation and MK-801, an irreversible use-dependent antagonist of NMDARs. Application of TBS in naïve slices evoked a transient potentiation. In contrast, the activation of ES-NMDARs evoked a robust LTD. These results suggest the involvement of ES-NMDARs in LTD induction.