Ohno M, Frankland P W, Chen A P, Costa R M, Silva A J
Departments of Neurobiology, Psychiatry and Psychology, Brain Research Institute, University of California, Los Angeles, California 90095-1761, USA.
Nat Neurosci. 2001 Dec;4(12):1238-43. doi: 10.1038/nn771.
Here we introduce a strategy in which pharmacology is used to induce the effects of recessive mutations. For example, mice heterozygous for a null mutation of the K-ras gene (K-ras+/-) show normal hippocampal mitogen-activated protein kinase (MAPK) activation, long-term potentiation (LTP) and contextual conditioning. However, a dose of a mitogen-activated/extracellular-signal-regulated kinase (MEK) inhibitor, ineffective in wild-type controls, blocks MAPK activation, LTP and contextual learning in K-ras+/- mutants. These indicate that K-Ras/MEK/MAPK signaling is critical in synaptic and behavioral plasticity. A subthreshold dose of NMDA receptor antagonists triggered a contextual learning deficit in mice heterozygous for a point mutation (T286A) in the alphaCaMKII gene, but not in K-ras+/- mutants, demonstrating the specificity of the synergistic interaction between the MEK inhibitor and the K-ras+/- mutation. This pharmacogenetic approach combines the high temporal specificity that pharmacological manipulations offer, with the molecular specificity of genetic disruptions.
在此，我们介绍一种策略，即利用药理学方法诱导隐性突变的效应。例如，K-ras基因无效突变的杂合小鼠（K-ras+/-）表现出正常的海马丝裂原活化蛋白激酶（MAPK）激活、长时程增强（LTP）和情境条件反射。然而，在野生型对照中无效的一定剂量的丝裂原活化/细胞外信号调节激酶（MEK）抑制剂，可阻断K-ras+/-突变体中的MAPK激活、LTP和情境学习。这些结果表明，K-Ras/MEK/MAPK信号传导在突触和行为可塑性中至关重要。亚阈值剂量的NMDA受体拮抗剂在αCaMKII基因点突变（T286A）的杂合小鼠中引发了情境学习缺陷，但在K-ras+/-突变体中未引发，这证明了MEK抑制剂与K-ras+/-突变之间协同相互作用的特异性。这种药物遗传学方法将药理学操作所提供的高时间特异性与基因破坏的分子特异性结合在一起。
