|Budget Amount *help
¥3,500,000 (Direct Cost : ¥3,500,000)
Fiscal Year 1999 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1998 : ¥3,000,000 (Direct Cost : ¥3,000,000)
A train of low-frequency afferent stimuli (LFS, 1 Hz, 1,000 pulses), given 60 min prior to a tetanus (100 Hz, 100 pulses), suppresses the induction of long-term potentiation (LTP suppression). Firstly, we investigated the effects of NMDA receptor antagonist (AP5) and adenosine A2 receptor antagonist (CP-66713), respectively, on LTP suppression in CA1 neurons of guinea pig hippocampal slices. When the LFS was delivered in the presence of AP5 (50 μM) or CP-66713 (10 μM), LTP suppression was inhibited, leading to successful LTP induction. Since activation of the adenosine A2 receptors facilitates CaィイD12+ィエD1 influx through the NMDA receptors, this result indicates that CaィイD12+ィエD1 influx through the NMDA receptors is essential for the mechanism of LTP suppression.
Secondly, we studied the intracellular CaィイD12+ィエD1 concentration ([CaィイD12+ィエD1]i ) during LTP induction at CA1 pyramidal neurons of mice lacking type 1 inositol-1, 4, 5-triphosphate receptors (IP3R1). The IP3 receptor acts as a channel of IP3-gated CaィイD12+ィエD1 release from intracellular calcium storage in hippocampal neurons. LTP suppression was not induced in CA1 neurons of mice lacing IP3R1, where [CaィイD12+ィエD1]i decrease during LTP induction was slower than in CA1 neurons of control wild-type mice. These indicate that LTP suppression in hippocampal CA1 neurons depends on both CaィイD12+ィエD1 influx through NMDA receptors and CaィイD12+ィエD1 efflux through IP3R1 during pre-conditioning LFSs. Then, it is possible that post-synaptic CaィイD12+ィエD1 efflux through IP3R1 during, or after, LFS, as well as CaィイD12+ィエD1 influx from the extracellular space, triggers signaling steps to quicken [CaィイD12+ィエD1]i decrease during LTP induction.