Inducible, pharmacogenetic approaches to the study of learning and memory

Nat Neurosci. 2001 Dec;4(12):1238-43. doi: 10.1038/nn771.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Avoidance Learning / drug effects
  • Avoidance Learning / physiology
  • Axons / drug effects
  • Axons / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / deficiency
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology
  • Electric Stimulation
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Fear / drug effects
  • Fear / physiology
  • Female
  • Genes, ras / drug effects*
  • Genes, ras / physiology
  • Heterozygote
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Learning / drug effects*
  • Learning / physiology
  • Long-Term Potentiation / drug effects*
  • Long-Term Potentiation / physiology
  • MAP Kinase Kinase 1
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / physiology
  • Male
  • Memory / drug effects*
  • Memory / physiology
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutation / drug effects*
  • Mutation / physiology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism

Substances

  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Protein-Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • Map2k1 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases