The effects of high Mg2+-to-Ca2+ ratios on frequency potentiation in hippocampal slices of young and aged rats

P. W. Landfield, T. A. Pitler, M. D. Applegate

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137 Scopus citations


1. 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. 2. 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. 3. 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. 4. 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. Aging also reduced the threshold for triggering the population spike by synaptic stimulation, whereas high Mg2+ elevated this threshold. 5. Intracellular studies indicated that high Mg2+-to-Ca2+ ratios can affect hippocampal activity during repetitive activation by actions on both postsynaptic membrane potential and EPSP potentiation. That is, the hyperpolarization that normally accompanies frequency potentiation was substantially reduced in high Mg2+-to-Ca2+ ratios, leading to greater initial postsynaptic depolarization and increased spike activation. The intracellular EPSP was significantly larger and more resistant to depression in high than in low Mg2+-to-Ca2+ ratios during repetitive stimulation. Several processes could account for this latter effect, including actions on release probability or on a recently described phenomenon of Ca2+-mediated inactivation of Ca2+ currents in hippocampal cells. 6. The data therefore suggest that at least two, and perhaps more, Ca2+-dependent processes regulate the transmission of information through hippocampal circuits during repetitive stimulation. High Mg2+-to-Ca2+ ratios appear to increase frequency potentiation by actions on each of these Ca2+-dependent mechanisms. 7. High Mg2+-to-Ca2+ ratios improved frequency potentiation proportionately more in aged than in young rat slices, and the effects of aging and high Mg2+ were opposed on most indexes of frequency potentiation. Thus there may be relatively greater activation of Ca2+-dependent processes in aged brain cells and this may impair the capacity of the aged brain to process information carried by higher frequency activity.

Original languageEnglish
Pages (from-to)797-811
Number of pages15
JournalJournal of Neurophysiology
Issue number3
StatePublished - 1986

ASJC Scopus subject areas

  • Neuroscience (all)
  • Physiology


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