Activation of Fyn tyrosine kinase in the mouse dorsal hippocampus is essential for contextual fear conditioning
Activation of Fyn tyrosine kinase in the mouse dorsal hippocampus is essential for contextual fear conditioning
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DOI：
10.1111/j.1460-9568.2008.06405.x
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发表时间：
2008-09-01
影响因子：
3.4
通讯作者：
Yuasa, Shigeki
中科院分区：
文献类型：
--
作者：
Isosaka, Tomoko;Hattori, Kotaro;Yuasa, Shigeki
Fyn-酪氨酸激酶缺陷小鼠在Morris水迷宫测试和海马长期增强（LTP）诱导中表现出缺陷，鉴于LTP被认为是记忆形成的神经基础，Fyn可能是海马依赖性记忆形成所必需的。然而，Fyn如何参与记忆形成的过程尚不清楚。为了研究Fyn在海马记忆形成中的作用，我们首先通过情境恐惧条件反射测试了Fyn缺陷小鼠的行为。把一只老鼠放在一个环境中，然后对它的脚进行电击，这样老鼠就会把这个环境和电击联系起来。我们发现fyn缺陷小鼠对环境的冷冻反应在条件反射后24小时受损。然后我们在条件反射后1小时测量冻结，发现他们的短期情境恐惧记忆也受损。我们用Western blotting检测情境恐惧条件反射后海马背侧组织Fyn的激活模式。Fyn激活在情境恐惧条件反射后5-10分钟达到峰值，并持续至少40分钟。同时还观察到包括NR2B在内的几种蛋白质的酪氨酸磷酸化增加，但在fyn缺陷小鼠中未观察到酪氨酸磷酸化增加。因此，Fyn缺陷小鼠的短期和长期（24小时）情境恐惧记忆均受损，并且在情境恐惧条件反射后，海马背侧Fyn的激活短暂增加。这些发现有力地表明Fyn信号通路的激活参与了海马体依赖性情境恐惧记忆的形成。
Fyn-tyrosine-kinase-deficient mice exhibit defects in the Morris water maze test and long-term potentiation (LTP) induction in the hippocampus, and given that LTP has been postulated as the neural basis for memory formation, Fyn may be required for hippocampus-dependent memory formation. However, how Fyn is involved in the process of memory formation is unclear. To investigate the role of Fyn in hippocampal memory formation, we first tested the behavior of Fyn-deficient mice by contextual fear conditioning. A mouse was placed in a context and a foot shock was delivered, so that the mouse associated the context with the shock. We found that the freezing response of Fyn-deficient mice to the context was impaired at 24 h after conditioning. We then measured freezing at 1 h after conditioning, and found that their short-term contextual fear memory was also impaired. We used Western blotting to examine the mode of Fyn activation in dorsal hippocampal tissue following contextual fear conditioning. Fyn activation peaked as early as 5-10 min after contextual fear conditioning and persisted for at least 40 min. Concomitant increases in tyrosine phosphorylation of several proteins, including NR2B, were also observed, but no increases in tyrosine phosphorylation were observed in Fyn-deficient mice. Thus, both short-term and long-term (24-h) contextual fear memory were impaired in Fyn-deficient mice, and Fyn activation in the dorsal hippocampus transiently increased after contextual fear conditioning. These findings strongly suggest that activation of the Fyn signaling pathway is involved in hippocampus-dependent formation of contextual fear memory.