PREGS induces LTP in the hippocampal dentate gyrus of adult rats via the tyrosine phosphorylation International Cooperative Research CREB signaling

An acute application of neurosteroid pregnenolone sulfate (PREGS) to hippocampal slices from adult rats induced a long-lasting potentiation (LLPPREGS) at the perforant path-granule cell synapse. As a partial mechanism of the LLPPREGS, we previously revealed that PREGS transiently increases the probability of presynaptic glutamate release via a sensitization of alpha 7-nicotinic acetylcholine receptor (alpha 7nAChR). We herein demonstrate that the LLPPREGS could be separated into two independent processes: the above-mentioned early presynaptic-origin short-term potentiation (STPPREGS) and a delayed postsynaptic N-methyl-D-aspartate receptor (NMDAr)-dependent long-term potentiation termed LTPPREGS. This study focused on the analysis of the signaling mechanism underlying the LTPPREGS. PREGS increased the tyrosine phosphorylation of NR2B, a subunit of NMDAr, and the NMDAr-mediated Ca2+ influx in the granule cells. The enhanced Ca2+ influx was largely attenuated by the NR2B subunit inhibitor ifenprodil and the Src kinase family inhibitor PP2. PREGS also triggered a persistent phosphorylation of extracellular signal-regulated kinase 2 (ERK2) followed by an ERK-dependent phosphorylation of cAMP-response element-binding protein (CREB), which was crucial for the LTPPREGS induction and was sensitive to ifenprodil. These results suggest that PREGS induces an acute increase in the NR2B tyrosine phosphorylation which enhances the Ca2+ influx through NMDAr, followed by an activation of the ERK/CREB signaling cascade that leads to LTPPREGS.