Ras/Raf/MEK/ERK (Ras-ERK) signaling has been shown to play an important role in fear acquisition. However, little information is known regarding the mechanisms that contribute to the regulation of this pathway in terms of the learning of conditioned fears. Ras Guanine Nucleotide Releasing Factor 2 (RasGRF2) is one of two guanine nucleotide exchange factors (GEF) that regulates the Ras-ERK signaling pathway in a Ca²⁺-dependent manner via control of the cycling of Ras isoforms between an inactive and active state. Here we sought to determine the role of RasGRF2 on contextual fear conditioning in RasGRF2 knockout (KO) and their wild type (WT) counterparts. Male KO and WT mice underwent a single session of contextual fear conditioning (12 min, 4 unsignaled shocks), followed by either daily 12-min retention trials or the molecular analysis of Ras activation and pERK1/2 activity. KO mice showed an impaired acquisition of contextual fear, as demonstrated by reduced freezing during fear conditioning and 24-hr retention tests relative to WT mice. Ras analysis following fear conditioning demonstrated a reduction in Ras activation in the hippocampus as well as a reduction in pERK1/2 in the CA1 region of the hippocampus in KO mice, suggesting that the decrease in fear conditioning in KO mice is at least in part due to the impairment of Ras-ERK signaling in the hippocampus during learning. These data indicate a role for RasGRF2 in contextual fear conditioning in mice that may be Ras-ERK-dependent.

Ras/Raf/MEK/ERK (Ras-ERK) 信号已被证明在恐惧获得中发挥重要作用。然而，关于在条件恐惧的学习方面有助于调节该途径的机制的信息知之甚少。Ras 鸟嘌呤核苷酸释放因子 2 (RasGRF2) 是调节 Ca ^{2+中 Ras-ERK 信号通路的两种鸟嘌呤核苷酸交换因子 (GEF) 之一}通过控制 Ras 异构体在非活性和活性状态之间的循环的依赖方式。在这里，我们试图确定 RasGRF2 在 RasGRF2 敲除 (KO) 及其野生型 (WT) 对应物的情境恐惧条件反射中的作用。雄性 KO 和 WT 小鼠经历了一次情境恐惧条件反射（12 分钟，4 次无信号电击），然后是每天 12 分钟的保留试验或 Ras 激活和 pERK1/2 活性的分子分析。KO 小鼠表现出对情境恐惧的获得受损，这可以通过相对于 WT 小鼠的恐惧条件反射和 24 小时保留测试期间减少的冻结来证明。恐惧条件反射后的 Ras 分析表明，KO 小鼠海马中的 Ras 激活减少以及海马 CA1 区域的 pERK1/2 减少，表明 KO 小鼠恐惧条件反射的减少至少部分是由于学习过程中海马中 Ras-ERK 信号传导的损害。这些数据表明 RasGRF2 在可能依赖于 Ras-ERK 的小鼠的情境恐惧条件反射中的作用。