Acquisition of Contextual Discrimination Involves the Appearance of a RAS-GRF1/p38 Mitogen-activated Protein (MAP) Kinase-mediated Signaling Pathway That Promotes Long Term Potentiation (LTP)
Acquisition of Contextual Discrimination Involves the Appearance of a RAS-GRF1/p38 Mitogen-activated Protein (MAP) Kinase-mediated Signaling Pathway That Promotes Long Term Potentiation (LTP)
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DOI：
10.1074/jbc.m113.471904
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发表时间：
2013-07-26
影响因子：
4.8
通讯作者：
Feig, Larry A.
中科院分区：
文献类型：
--
作者：
Jin, Shan-Xue;Arai, Junko;Feig, Larry A.
RAS-GRF 1是一种鸟嘌呤核苷酸交换因子，能够激活RAS和RAC GTP酶，以响应钙水平升高。我们先前表明，从1个月大开始，RAS-GRF 1介导NMDA型谷氨酸受体（NMDAR）诱导小鼠海马CA 1区的长期抑郁。在这里，我们表明，从2个月大开始，当小鼠第一次获得的能力，以区分密切相关的上下文，RAS-GRF 1开始有助于诱导长时程增强（LTP）在CA 1海马介导的钙渗透，AMPA型谷氨酸受体（CP-AMPAR）的行动。令人惊讶的是，CP-AMPAR通过RAS-GRF 1诱导LTP是通过激活p38 MAP激酶而不是ERK MAP激酶来实现的，后者更常与LTP相关。此外，上下文歧视被阻断的Ras-Grf 1表达，特别是在CA 1海马，p38 MAP激酶抑制剂注入到CA 1海马，或注射抑制剂的CP-AMPAR。这些研究结果表明，CA 1海马在发育依赖的能力，区分密切相关的情况下，通过一个新的LTP支持信号通路的外观。
RAS-GRF1 is a guanine nucleotide exchange factor with the ability to activate RAS and RAC GTPases in response to elevated calcium levels. We previously showed that beginning at 1 month of age, RAS-GRF1 mediates NMDA-type glutamate receptor (NMDAR)-induction of long term depression in the CA1 region of the hippocampus of mice. Here we show that beginning at 2 months of age, when mice first acquire the ability to discriminate between closely related contexts, RAS-GRF1 begins to contribute to the induction of long term potentiation (LTP) in the CA1 hippocampus by mediating the action of calcium-permeable, AMPA-type glutamate receptors (CP-AMPARs). Surprisingly, LTP induction by CP-AMPARs through RAS-GRF1 occurs via activation of p38 MAP kinase rather than ERK MAP kinase, which has more frequently been linked to LTP. Moreover, contextual discrimination is blocked by knockdown of Ras-Grf1 expression specifically in the CA1 hippocampus, infusion of a p38 MAP kinase inhibitor into the CA1 hippocampus, or the injection of an inhibitor of CP-AMPARs. These findings implicate the CA1 hippocampus in the developmentally dependent capacity to distinguish closely related contexts through the appearance of a novel LTP-supporting signaling pathway.