Metaplastic LTP inhibition after LTD induction in CA1 hippocampal slices involves NMDA receptor-mediated neurosteroidogenesis

Long-term depression (LTD) induced by low-frequency electrical stimulation (LFS) in the CA1 region of the hippocampus is a form of synaptic plasticity thought to contribute to learning and memory and to the pathophysiology of neuropsychiatric disorders. In naïve hippocampal slices from juvenile rats, we previously found that LTD induction can impair subsequent induction of long-term potentiation (LTP) via a form of N-methyl-D-aspartate receptor (NMDAR)-dependent metaplasticity, and have recently observed that pharmacologically induced NMDAR-dependent LTP inhibition involves 5α-reduced neurosteroids that augment the actions of γ-aminobutyric acid (GABA). In this study, we found that both LFS-induced LTD and subsequent inhibition of LTP induction involve neurosteroid synthesis via NMDAR activation. Furthermore, the timing of 5α -reductase inhibition relative to LFS can dissociate effects on LTD and metaplastic LTP inhibition. These findings indicate that 5α -reduced neurosteroids play an important role in synaptic plasticity and synaptic modulation in the hippocampus.