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 αCaMKII 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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We thank S.A. Josselyn, N.B. Fedorov and K.P. Giese for discussions, and R. Chen and M. Lacuesta for help with genotyping. We also thank J.M. Trzaskos (DuPont Pharmaceuticals Research Laboratories) and T. Jacks (Department of Biology, MIT) for donating SL327 and K-ras+/− mutants, respectively. This work was funded by grants from the McKnight Foundation, Merck Foundation and the NIH (P01HD33098 and AG13622) to A.J.S. M.O. was partially supported by a research fellowship from the Uehara Memorial Foundation for Life Sciences.
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Ohno, M., Frankland, P., Chen, A. et al. Inducible, pharmacogenetic approaches to the study of learning and memory. Nat Neurosci 4, 1238–1243 (2001). https://doi.org/10.1038/nn771
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