1. Our results indicate that there are two distinct components of long- term potentiation (LTP) induced by the K+ channel blocker tetraethylammonium chloride (TEA) at synapses of hippocampal CA1 pyramidal neurons. Preincubation of hippocampal slices in the N-methyl-D aspartate (NMDA) receptor antagonist D,L-2-amino-5 phosphonovalerate (D,L-APV, 50 μM), reduced the magnitude of TEA LTP. In addition, the L-type voltage-dependent Ca2+ channel (VDCC) antagonist nifedipine (10 μM) attenuated TEA LTP. Only the combined application of D,L-APV plus nifedipine blocked the induction of TEA LTP. 2. Occlusion experiments demonstrated that saturation of VDCC- dependent TEA LTP did not reduce or occlude NMDA-receptor-dependent TEA LTP. These results indicate that the mechanisms underlying VDCC and NMDA receptor components of TEA LTP are different and do not share a common saturable mechanism. 3. TEA LTP was strictly dependent on NMDA receptor activity in slices with CA3-CA1 connections severed (isolated CA1 slices). In contrast to results obtained in slices with intact CA3-CA1 connections, the NMDA receptor antagonists APV (50 μM) or MK-801 dizocilpine (10 μM) completely blocked TEA LTP in isolated CA1. Consistent with this observation, the properties of TEA LTP in isolated CA1 were very similar to other types of NMDA-receptor- dependent plasticity such as tetanus-induced LTP; TEA LTP required presynaptic stimulation, displayed pathway specificity, and was occluded by tetanus-induced LTP. 4. A variety of conditions were tested to facilitate the induction of VDCC-dependent TEA LTP in isolated CA1 slices. High-frequency stimulation (80-ms pulses at 25 Hz) to Schaffer collaterals or CA1 axons (i.e., antidromic stimulation) in conjunction with TEA application induced LTP in the presence of APV (100-200 μM). This potentiation was completely blocked by the combined application of APV (100-200 μM) and nifedipine (50 μM), indicating that induction of VDCC-dependent TEA LTP is frequency dependent, similar to other types of VDCC-dependent plasticity. 5. Using a 25-Hz stimulation protocol in two pathway experiments, we observed that induction of VDCC-dependent TEA LTP was not pathway specific. which contrasts with NMDA-receptor-dependent TEA LTP and suggests that the route of Ca2+ entry during LTP induction can determine synapse specificity. 6. These results demonstrate that different Ca2+-dependent processes may be activated by VDCCs and NMDA receptors that induce long-lasting potentiation with different properties.
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