期刊
NATURE NEUROSCIENCE
卷 4, 期 12, 页码 1238-1243出版社
NATURE AMERICA INC
DOI: 10.1038/nn771
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资金
- NIA NIH HHS [AG13622] Funding Source: Medline
- NICHD NIH HHS [P01HD33098] Funding Source: Medline
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 alpha CaMKII 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.
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