Modulatory metaplasticity induced by pregnenolone sulfate in the rat hippocampus: a leftward shift in LTP/LTD-frequency curve.

We recently have found that an acute application of the neurosteroid pregnenolone sulfate (PREGS) at 50 muM to rat hippocampal slices induces a long-lasting potentiation (LLP(PREGS)) via a sustained ERK2/CREB activation at perforant-path/granule-cell synapses in the dentate gyrus. This study is a follow up to investigate whether the expression of LLP(PREGS) influences subsequent frequency-dependent synaptic plasticity. Conditioning electric stimuli (CS) at 0.1-200 Hz were given to the perforant-path of rat hippocampal slices expressing LLP(PREGS) to induce long-term potentiation (LTP) and long-term depression (LTD). The largest LTP was induced at about 20 Hz-CS, which is normally a subthreshold frequency, and the largest LTD at 0.5 Hz-CS, resulting in a leftward-shift of the LTP/LTD-frequency curve. Furthermore, the level of LTP at 100 Hz-CS was significantly attenuated to give band-pass filter characteristics of LTP induction with a center frequency of about 20 Hz. The LTP induced by 20 Hz-CS (termed 20 Hz-LTP) was found to be postsynaptic origin and dependent on L-type voltage-gated calcium channel (L-VGCC) but not on N-methyl-D-aspartate receptor (NMDAr). Moreover, the induction of 20 Hz-LTP required a sustained activation of ERK2 that had been triggered by PREGS. In conclusion, the transient elevation of PREGS is suggested to induce a modulatory metaplasticity through a sustained activation of ERK2 in an L-VGCC dependent manner.