In some central systems, excitatory postsynaptic potential (EPSP) amplitude increases substantially during repetitive synaptic stimulation ("frequency potentiation"), as does the probability of spike generation. An apparently analogous phenomenon at the neuromuscular junction ("frequency facilitation") depends on residual Ca2+ in nerve terminals. However, the mechanisms of central frequency potentiation are not completely defined and it is therefore not clear whether the patterns of Ca2+-dependent synaptic plasticity are fully analogous in central and peripheral systems. In addition, an age-related deficit in hippocampal frequency potentiation has been previously described, and the degree of sensitivity of this deficit to Mg2+-to-Ca2+ balance could yield important insights into its nature. In these studies, we used the hippocampal slice preparation to examine the effects of varying Mg2+-to-Ca2+ ratios in the artificial cerebrospinal fluid (ACF) on frequency potentiation in aged and young rats. Extracellular and intracellular methods were used to assess the responses of hippocampal CA1 neurons during orthodromic stimulation of the monosynaptic Schaffer-commissural pathway. In experiment 1, frequency potentiation of the hippocampal population spike during 7-Hz stimulation was found to be significantly greater in an ACF with a high Mg2+-to-Ca2+ ratio (2.7) than in an ACF with a normal Mg2+-to-Ca2+ ratio (0.5), for both young and aged rat slices. Aged slices exhibited less frequency potentiation than young in both media. In experiment 2, the field EPSP and population spike were monitored concurrently, and the differences in Mg2+-to-Ca2+ ratio between the high Mg2+-to-Ca2+ ACF ratio (2.0) and normal Mg2+-to-Ca2+ ACF ratio (1.0) were reduced, to determine whether aged and young brains differed in sensitivity to smaller variations in Mg2+-to-Ca2+ balance. Under these conditions, the effects of high Mg2+-to-Ca2+ ratios on frequency potentiation (at 7 Hz) were found to be most pronounced in aged rat slices, particularly for potentiation of the spike. No effects were seen of age or Mg2+-to-Ca2+ ratios on presynaptic fiber volley amplitudes. Field EPSP (but not spike) amplitudes were reduced with aging, in an input-output (I/O) stimulation series at control frequency (0.2 Hz). However, the high Mg2+-to-Ca2+ ACF ratio of (2.0), which improved field EPSP frequency potentiation, did not decrease control field EPSP amplitudes in the I/O series. Therefore, the effects of high MG2+-to-Ca2+ ACF ratio on brain frequency potentiation seem to be mediated in part by mechanisms other than the classical reduction of release probability.(ABSTRACT TRUNCATED AT 400 WORDS)