R-Ras contributes to LTP and contextual discrimination.
R-Ras contributes to LTP and contextual discrimination.
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DOI：
10.1016/j.neuroscience.2014.07.010
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发表时间：
2014-09-26
期刊：
影响因子：
3.3
通讯作者：
Feig, L. A.
中科院分区：
文献类型：
--
作者：
Darcy, M. J.;Jin, S. -X.;Feig, L. A.
区分密切相关环境的能力是海马体依赖学习的一种特殊形式，它可能在某些神经退行性疾病（如阿尔茨海默氏症和唐氏综合症）中受损。然而，调控这种学习形式的信号通路却知之甚少。先前的研究表明，钙依赖性交换因子Ras- grf1是Rac、Ras和R-Ras gtpase的激活剂，对这种形式的学习和记忆很重要。此外，区分上下文的能力与Ras-GRF1通过激活p38 Map激酶促进高频刺激(HFS)-LTP的能力有关。在这里，我们通过在海马背侧CA1区域使用病毒递送的靶向R-Ras的mirna，并观察到受损的上下文辨别，证明R-Ras参与了这种形式的学习。与GRF1的缺失一样，CA1中R-Ras的下调也会损害HFS-LTP和p38 Map激酶的诱导。然而，实验表明R-Ras参与HFS-LTP是上下文歧视所必需的，与Ras-GRF1无关。因此，R-Ras是海马依赖性LTP以及在某些形式的神经退行性疾病中受到影响的学习和记忆的一种新型调节剂。
The ability to discriminate between closely related contexts is a specific form of hippocampal-dependent learning that may be impaired in certain neurodegenerative disorders such as Alzheimer's and Down Syndrome. However, signaling pathways regulating this form of learning are poorly understood. Previous studies have shown that the calcium-dependent exchange factor Ras-GRF1, an activator of Rac, Ras and R-Ras GTPases, is important for this form of learning and memory. Moreover, the ability to discriminate contexts was linked to the ability of Ras-GRF1 to promote high-frequency stimulation (HFS)-LTP via the activation of p38 Map kinase. Here, we show that R-Ras is involved in this form of learning by using virally-delivered miRNAs targeting R-Ras into the CA1 region of dorsal hippocampus and observing impaired contextual discrimination. Like the loss of GRF1, knockdown of R-Ras in the CA1 also impairs the induction of HFS-LTP and p38 Map kinase. Nevertheless, experiments indicate that this involvement of R-Ras in HFS-LTP that is required for contextual discrimination is independent of Ras-GRF1. Thus, R-Ras is a novel regulator of a form of hippocampal-dependent LTP as well as learning and memory that is affected in certain forms of neurodegenerative diseases.
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