Chronic DHEAS administration facilitates hippocampal long-term potentiation via an amplification of Src-dependent NMDA receptor signaling
Chronic DHEAS administration facilitates hippocampal long-term potentiation via an amplification of Src-dependent NMDA receptor signaling
复制标题
DOI：
10.1016/j.neuropharm.2006.05.011
复制
发表时间：
2006-09-01
影响因子：
4.7
通讯作者：
Sokabe, Masahiro
中科院分区：
文献类型：
--
作者：
Chen, Ling;Miyamoto, Yoshiaki;Sokabe, Masahiro
脱氢表雄酮硫酸盐(DHEAS)对记忆和认知能力有明显的影响。最近，我们报道了重复给予DHEAS降低了在大鼠海马Schaffer侧支-CA1突触中诱导活性依赖的长时程增强(LTP)的阈值脉冲数量，其中对正常大鼠的亚阈值高频刺激(HFS，30个脉冲，100 Hz)可以在DHEAS处理的大鼠中诱导出强大的LTP(Chen等，2006)。在这里，我们报告亚阈值HFS可以在DHEAS处理的大鼠中触发Src和ERK2的磷酸化，但在对照组大鼠中不能。我们在DHEAS处理的大鼠脑片中发现，NMDA诱导的CA1锥体神经元细胞内钙([Ca+](I))瞬变显著增强，这对Src和ERK2的磷酸化是必不可少的。ERK2的激活是DHEAS促进的LTP所必需的，ERK2是Src家族激酶下游因子。Src家族激酶抑制剂PP2，而不是其失活的同系物PP3，可减弱NMDA诱导的[Ca~(2+)](I)升高，并取消DHEAS促进的LTP。这些结果表明，慢性给予DHEAS使NMDAR(NMDAR)处于增强状态，即使在阈值以下的HFS也能引起足够水平的[Ca~(2+)](I)升高以诱导LTP。亚阈值HFS增强的[Ca~(2+)]i瞬变可能触发Src的磷酸化，从而进一步增强NMDAR，随后激活ERK2和LTP诱导。这种新的突触后NMDAR/Src通过“NMDAR-Ca~(2+)-GT；SRE->；NMDAR-Ca~(2+)”循环介导的信号放大可能在DHEAS促进的LTP诱导中发挥关键作用。(C)2006爱思唯尔有限公司。保留所有权利。
Dehydroepiandrosterone sulfate (DHEAS) has well characterized effects on memory and cognitive performances. Recently we have reported that repetitive administration of DHEAS lowers the threshold pulse number in inducing activity-dependent long-term potentiation (LTP) in rat hippocampal Schaffer collateral-CA1 synapses, in which a sub-threshold high frequency stimulation (HFS, 30 pulses at 100 Hz) for normal rats could induce robust LTP in DHEAS-treated rats (Chen et al., 2006). Here we report that the sub-threshold HFS could trigger the phosphorylation of Src and ERK2 in the DHEAS-treated rats, but not in control rats. We found in slices obtained from the DHEAS-treated rats that NMDA-induced intracellular Ca2+([Ca2+](i)) transients in CA1 pyramidal neurons were significantly potentiated, which was essential for the Src and ERK2 phosphorylations. The activation of ERK2, a downstream factor of Src family kinase, was required for the DHEAS-facilitated LTP. The Src family kinase inhibitor PP2, but not its inactive homologue PP3, attenuated the NMDA-induced [Ca2+](i) increase and abolished the DHEAS-facilitated LTP. These findings suggest that the chronic administration of DHEAS brings the NMDA receptor (NMDAr) to a potentiated state that causes an enough level of [Ca2+](i) increase for LTP induction even by the sub-threshold HFS. The potentiated [Ca2+]i transient by the sub-threshold HFS may trigger the Src phosphorylation that will further potentiate NMDAr followed by an activation of ERK2 and LTP induction. This novel postsynaptic NMDAr/Src-mediated signal amplification through "NMDAr-Ca2+ -> Sre -> NMDAr-Ca2+" cycle may play a pivotal role in the DHEAS-facilitated LTP induction. (c) 2006 Elsevier Ltd. All rights reserved.