ISOLATED NMDA RECEPTOR-MEDIATED SYNAPTIC RESPONSES EXPRESS BOTH LTP AND LTD

1. The possibility of use-dependent, long-lasting modifications of pharmacologically isolated N-methyl-D-aspartate (NMDA) receptor-mediated synaptic transmission was examined by intracellular recordings from granule cells of the hippocampal dentate gyrus in vitro. In the presence of the non-NMDA receptor antagonist 6-cyano-7-nitroquinaxaline-2,3-dione (CNQX, 10-mu-M) robust, long-term potentiation (LTP) of NMDA receptor-mediated synaptic potentials was induced by brief, high (50 Hz) and lower (10 Hz) frequency tetanic stimuli of glutamatergic afferents (60 +/- 6%, n = 8, P < 0.001 and 43 +/- 12%, n = 3, P < 0.05, respectively). 2. Hyperpolarization of granule cell membrane potential to - 100 mV during 50-Hz tetanic stimuli reversibly blocked the induction of LTP (- 6 +/- 2%, n = 6, P > 0.05) indicating that simultaneous activation of pre- and postsynaptic elements is a prerequisite for potentiation of NMDA receptor-mediated synaptic transmission. In contrast, hyperpolarization of the granule cell membrane potential to - 100 mV during 10-Hz tetanic stimuli resulted in long-term depression (LTD) of NMDA receptor-mediated synaptic potentials (- 34 +/- 8%, n = 8, P < 0.01). 3. We also studied the role of [Ca2+]i in the induction of LTP and LTD of NMDA receptor-mediated synaptic responses. Before tetanization, [Ca2+]i was buffered by iontophoretic injections of bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA). BAPTA completely blocked the induction of LTP (3 +/- 5%, n = 13) and partially blocked LTD (- 14.8 +/- 6%, n = 10). The magnitude of LTD expressed by BAPTA-loaded cells was significantly smaller than that expressed by control cells (P < 0.05). 4. These findings provide the first evidence for the induction of both LTP and LTD of NMDA receptor-mediated synaptic transmission and demonstrate that the level of postsynaptic depolarization can determine which of the two forms of synaptic plasticity is expressed in response to an identical input. Furthermore, our results strongly suggest that postsynaptic Ca2+ influx is essential not only for induction of LTP but also for induction of LTD of NMDA receptor/channel function.