Molecular coupling required for intracellular calcium release that regulates synaptic depression

点击翻译按钮获取中文摘要

Induction of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), is believed to require synaptically induced Ca2+ rises. Although LTP is thought to be induced by large rises of Ca2+, two different mechanisms have been proposed for LTD induction : one is LTD induction by intracellular Ca2+ release, whereas the other mechanism depends on moderate rises of Ca2+ from whatever calcium sources. We studied whether both of these LTD induction mechanisms operate and, if so, how these mechanisms cooperate. Under pharmacological manipulations, LTD induction was attempted by using conditioning stimulations of different frequencies, and relationship were seeked for between the magnitude of LTD and the extent of intracellular Ca2+ rises. With 0.5-1.0 Hz stimulation, LTD induction depends crucially on the calcium source but not on the amount of calcium rise, and calcium release facilitated LTD induction with calcium influx via L-type calcium channel inhibiting it … More . At 0.5 Hz, a ryanodine receptor agonist, caffeine, and an L-type Ca2+ channel blocker, nifedipine, both enhanced the magnitude of LTD. At 1Hz, an internal Ca2+ stone depletor, thapsigargin and an L-type Ca2+ channel activator, S (-)-BAY K8644, both decreased LTD magnitude. At 2Hz, however, the change in synaptic efficiency was in parallel with the amount of Ca2+ rises. From these findings, we conclude that the two mechanisms are both involved in LTD induction but separately at two different levels of postsynaptic activation : the source dependent mechanism operate at lower postspaptic activation ranges than the calcium concentration dependent mechanism does. Relationship between LTD induction mechanisms detailed above and the novel calcium release mechanisms that we have observed (IP3-assisted CICR) has also been investigated. The results suggested a hitherto unknown role of the adaptor protein Homerla in enabling activity-dependent enhancement of calcium signal, which is likely to interfere with rules of synaptic modification. Less