Persistent increase of hippocampal presynaptic axon excitability after repetitive electrical stimulation: Dependence on N-methyl-D-aspartate receptor activity, nitric-oxide synthase, and temperature

The electrical excitability of Schaffer collateral axons and/or terminals was studied in hippocampal slices by monitoring single, CA3 pyramidal neurons activated antidromically from CA1 stratum radiatum. At 22°C, weak, repetitive stimulation with as few as 10 impulses at 2 Hz led to a robust lowering of the antidromic activation threshold that lasted >30 min. The effect was completely absent at 32°C and was blocked by both the N-methyl- D-aspartate receptor antagonist, 2-amino-5-phosphonovalerate and the inhibitor of nitric-oxide synthase, L-nitroarginine methyl ester. Such threshold lowering would alter the variance of synaptic responses from axons stimulated in the variable excitation region of their input-output functions. These results thus raise important doubts about the interpretation of experiments in which the so-called minimal-stimulation method has been used at reduced temperature to infer changes in quantal transmission during hippocampal long-term potentiation. In the present experiments, no changes were observed in the estimate of excitatory postsynaptic potential quantal content in long-term potentiation experiments at either temperature, which could not be accounted for by an artifactual, temperature-dependent change in the responsiveness of presynaptic axons.