Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Avoidance Learning / drug effects
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Avoidance Learning / physiology
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Axons / drug effects
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Axons / metabolism
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / deficiency
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Conditioning, Psychological / drug effects
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Conditioning, Psychological / physiology
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Electric Stimulation
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / physiology
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Fear / drug effects
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Fear / physiology
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Female
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Genes, ras / drug effects*
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Genes, ras / physiology
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Heterozygote
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Hippocampus / drug effects*
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Hippocampus / metabolism
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Learning / drug effects*
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Learning / physiology
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Long-Term Potentiation / drug effects*
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Long-Term Potentiation / physiology
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MAP Kinase Kinase 1
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MAP Kinase Signaling System / drug effects*
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MAP Kinase Signaling System / physiology
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Male
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Memory / drug effects*
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Memory / physiology
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Mutation / drug effects*
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Mutation / physiology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
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Receptors, N-Methyl-D-Aspartate / metabolism
Substances
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Enzyme Inhibitors
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Excitatory Amino Acid Antagonists
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Receptors, N-Methyl-D-Aspartate
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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Map2k1 protein, mouse
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Mitogen-Activated Protein Kinase Kinases