Activation of inositol 1, 4, 5-trisphosphate receptors during preconditioning low-frequency stimulation leads to reversal of long-term potentiation in hippocampal CA1 neurons

We investigated the role of inositol 1, 4, 5-trisphosphate receptors (IP3Rs) that were activated during preconditioning low-frequency afferent stimulation (LFS) in the subsequent induction of synaptic plasticity in CA1 neurons in hippocampal slices from mature guinea pigs. In standard perfusate, long-term potentiation (LTP) was induced in the field excitatory postsynaptic potential (EPSP) by the delivery of LFS (80 pulses at 1 Hz), and was reversed by an identical LFS applied 20 min later. However, when CA1 synapses were preconditioned in the presence of an IP3R antagonist and stimulated by the second LFS in the absence of the antagonist, LTP was not reversed, but was increased, by the second LFS. In addition, when CA1 synapses were preconditioned in standard solution, but stimulated by the second LFS in the presence of an N-methyl-d-aspartate receptor (NMDAR) antagonist, LTP was again not reversed, but increased. The excitatory postsynaptic current (EPSC) through NMDARs recorded from CA1 pyramidal neurons increased significantly 20 min after a single LFS and this increase was inhibited when the LFS was delivered in the presence of an IP3R antagonist or a Ca2+/calmodulin-dependent protein kinase II inhibitor. These results suggest that activation of IP3Rs by a preconditioning LFS results in postsynaptic protein phosphorylation and/or enhancement of NMDAR activation during a subsequent LFS, leading to reversal of LTP in the field EPSP in hippocampal CA1 neurons.

▶LTP reversal induced by sequential delivery of two LFSs of 80 pulses at 1 Hz. ▶Activation of IP3 receptors by the first LFS may result in protein phosphorylation. ▶Protein phosphorylation may result in enhancement of NMDA receptor activation. ▶Ca2+ influx through NMDA receptors during the second LFS leads to reversal of LTP.