RASopathies are neuro-cardio-facio-cutaneous disorders stemming from mutations in genes regulating the RAS-MAPK pathway. Legius syndrome is a rare RASopathy disorder caused by mutations in the SPRED1 gene. SPRED1 protein negatively regulates activation of Ras by inhibiting RAS/RAF and by its interaction with neurofibromin, a Ras GTPase-activating protein (RAS-GAP). Cognitive impairments have been reported in Legius syndrome as well as in other RASopathy disorders. Modelling these cognitive deficits in a Spred1 mouse model for Legius syndrome has demonstrated spatial learning and memory deficits, but other cognitive domains remained unexplored. Here, we attempted to utilize a cognitive touchscreen battery to investigate if Spred1^−/− mice exhibit deficits in other cognitive domains. We show that Spred1^−/− mice had heterogeneous performance in instrumental operant learning, with a large subgroup (n = 9/20) failing to reach the standard criterion on touchscreen operant pretraining, precluding further cognitive testing. To examine whether targeting the RAS-MAPK signalling pathway could rescue these cognitive impairments, Spred1^−/− mice were acutely treated with the clinically relevant mitogen-activated protein kinase (MEK) inhibitor PD325901. However, MEK inhibition did not improve their instrumental learning. We conclude that Spred1^−/− mice can model severe cognitive impairments that cannot be reversed in adulthood.

中文翻译：

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Spred1-/- 小鼠的仪器学习受损，一种罕见的 RASopathy 模型

RASopathies 是由调节 RAS-MAPK 通路的基因突变引起的神经-心脏-面部-皮肤疾病。Legius 综合征是一种罕见的 RASopathy 疾病，由 SPRED1 基因突变引起。SPRED1 蛋白通过抑制 RAS/RAF 及其与神经纤维蛋白（一种 Ras GTP 酶激活蛋白 (RAS-GAP)）的相互作用来负调节 Ras 的激活。Legius 综合征以及其他 RASopathy 疾病中都有认知障碍的报道。在 Legius 综合征的Spred1小鼠模型中对这些认知缺陷进行建模已经证明了空间学习和记忆缺陷，但其他认知领域仍未探索。在这里，我们尝试利用认知触摸屏电池来调查Spred1 ^-/-小鼠在其他认知领域表现出缺陷。我们表明，Spred1 ^-/-小鼠在工具性操作学习方面表现不一，有一个较大的亚组 ( n  = 9/20) 未能达到触摸屏操作性预训练的标准标准，从而排除了进一步的认知测试。为了检查靶向 RAS-MAPK 信号通路是否可以挽救这些认知障碍，Spred1 ^-/-小鼠接受了临床相关的丝裂原活化蛋白激酶 (MEK) 抑制剂 PD325901 的急性治疗。然而，MEK 抑制并没有改善他们的器乐学习。我们得出结论，Spred1 ^-/-小鼠可以模拟成年后无法逆转的严重认知障碍。