Nature Neuroscience4, 1238 - 1243 (2001)
Published online: 19 November 2001; | doi:10.1038/nn771
Inducible, pharmacogenetic approaches to the study of learning and memory
Masuo Ohno, Paul W. Frankland, Adele P. Chen, Rui M. Costa
& Alcino J. Silva
Departments of Neurobiology, Psychiatry and Psychology, Brain Research Institute, University of California, Los Angeles, California 90095-1761, USA
Correspondence should be addressed to Alcino J. Silva silvaa@ucla.edu
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 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.
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.
