Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1
Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1
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DOI：
10.1038/nature711
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发表时间：
2002-01-31
期刊：
影响因子：
64.8
通讯作者：
Silva, AJ
中科院分区：
文献类型：
--
作者：
Costa, RM;Federov, NB;Silva, AJ
I型神经纤维瘤病（NF1）是导致人类学习缺陷的最常见的单基因疾病之一(1)。携带Nf1基因杂合零突变（Nf1(+/-)）的小鼠表现出与Nf1相关的学习缺陷的重要特征（参考文献2）。尽管神经纤维蛋白具有几种已知的特性和功能，包括Ras gtpase激活蛋白活性（3,4），腺苷酸环化酶调节（5,6）和微管结合(7)，但尚不清楚其中哪些对小鼠和人类的学习至关重要。本研究表明，Nf1（+/-）小鼠的学习缺陷可以通过降低Ras功能的遗传和药理学操作来挽救。我们还发现Nf1（+/-）小鼠增加了GABA （γ -氨基丁酸）介导的抑制和长期增强的特异性缺陷，这两者都可以通过降低Ras功能来逆转。我们的研究结果表明，与NF1相关的学习缺陷可能是由Ras活性过高引起的，Ras活性过高导致gaba介导的抑制增加导致长期增强功能受损。我们的研究结果对NF1相关学习缺陷治疗的发展具有启示意义。
Neurofibromatosis type I (NF1) is one of the most common single-gene disorders that causes learning deficits in humans(1). Mice carrying a heterozygous null mutation of the Nf1 gene (Nf1(+/-)) show important features of the learning deficits associated with NF1 (ref. 2). Although neurofibromin has several known properties and functions, including Ras GTPase-activating protein activity(3,4), adenylyl cyclase modulation(5,6) and microtubule binding(7), it is unclear which of these are essential for learning in mice and humans. Here we show that the learning deficits of Nf1(+/-) mice can be rescued by genetic and pharmacological manipulations that decrease Ras function. We also show that the Nf1(+/-) mice have increased GABA (gamma-amino butyric acid)-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Our results indicate that the learning deficits associated with NF1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. Our findings have implications for the development of treatments for learning deficits associated with NF1.