The magnitude of hippocampal long term depression depends on the synaptic location of activated NR2-containing N-methyl-d-aspartate receptors

Activation of N-methyl-d-aspartate receptors (NMDARs) is the first step in the induction of certain forms of synaptic plasticity in the hippocampus. In the adult rat hippocampus, NMDARs are composed almost exclusively of NR1 and NR2 subunits with NR1 subunits being mainly associated with either NR2A and/or NR2B subunits. The role played by the different subunits in synaptic plasticity is still controversial. In the present study, we used two different long term depression (LTD) –inducing protocols (electrical and chemical stimulation) to show that activation of NR2A-containing NMDAR subunits leads to the induction of LTD. We also demonstrated that extrasynaptic NR2B-containing NMDARs regulate the magnitude of LTD by exerting a control over the function of synaptic NR2A-containing NMDARs while having no effect on plasticity in the absence of synaptic receptor activation. Taken as a whole, these experiments demonstrate that NMDAR subunits play different roles according to their nature (NR2A or NR2B) and location (synaptic versus extrasynaptic). This sheds new light on the functional role of extrasynaptic NR2B containing-NMDARs. These results are particularly important for a better understanding of certain pathological disorders associated with glutamatergic overactivity.