LTP induction dependent on activation of Ni2+-sensitive voltage-gated calcium channels, but not NMDA receptors, in the rat dentate gyrus in vitro

A N-methyl-D-aspartate receptor (NMDAR)-independent long-term potentiation (LTP) has been investigated in the dentate gyrus of the hippocampus in vitro in the presence of the NMDAR antagonist, D-2-amino-phosphonopentanoate (50-100 mu M), at a concentration that completely blocked NMDAR-mediated excitatory postsynaptic currents (EPSCs). LTP of patch-clamped EPSCs was induced by pairing low-frequency evoked EPSCs (1 Hz) with depolarizing voltage pulses designed to predominately open low-voltage-activated (LVA) Ca2+ channels. Voltage pulses alone induced only a short-term potentiation. The LTP was blocked by intracellular application of the rapid Ca2+ chelator bis-(O-aminophenoxy)N, N, N', N'-tetraacetic acid, demonstrating that a rise in intracellular Ca2+ is required for the NMDAR-independent LTP induction. The NMDAR-independent LTP induction also was blocked by Ni2+ at a low extracellular concentration (50 mu M), which is known to strongly block LVA Ca2+ channels. However, Ni2+ did not inhibit the NMDAR-dependent LTP induced by high-frequency stimulation (HFS). The NMDAR-independent LTP induction was not blocked by high concentrations of the L-type Ca2+ channel blocker nifedipine (10 mu M). The NMDAR-independent LTP was inhibited by the metabotropic glutamate receptor ligand (+)-alpha-methyl-4-carboxyphenylglycine . These experiments demonstrate the presence of a NMDAR-independent LTP induced by Ca2+ influx via Ni2+-sensitive, nifedipine-insensitive voltage-gated Ca2+ channels, probably LVA Ca2+ channels. Induction of the NMDAR-independent LTP was inhibited by prior induction of HFS-induced NMDAR-dependent LTP, demonstrating that although the NMDAR-dependent and NMDAR-independent LTP use a different Ca2+ channel for Ca2+ influx, they share a common intracellular pathway.