Insulin receptor substrate 2 is a negative regulator of memory formation

Learn Mem. 2011 May 19;18(6):375-83. doi: 10.1101/lm.2111311. Print 2011 Jun.

Abstract

Insulin has been shown to impact on learning and memory in both humans and animals, but the downstream signaling mechanisms involved are poorly characterized. Insulin receptor substrate-2 (Irs2) is an adaptor protein that couples activation of insulin- and insulin-like growth factor-1 receptors to downstream signaling pathways. Here, we have deleted Irs2, either in the whole brain or selectively in the forebrain, using the nestin Cre- or D6 Cre-deleter mouse lines, respectively. We show that brain- and forebrain-specific Irs2 knockout mice have enhanced hippocampal spatial reference memory. Furthermore, NesCreIrs2KO mice have enhanced spatial working memory and contextual- and cued-fear memory. Deletion of Irs2 in the brain also increases PSD-95 expression and the density of dendritic spines in hippocampal area CA1, possibly reflecting an increase in the number of excitatory synapses per neuron in the hippocampus that can become activated during memory formation. This increase in activated excitatory synapses might underlie the improved hippocampal memory formation observed in NesCreIrs2KO mice. Overall, these results suggest that Irs2 acts as a negative regulator on memory formation by restricting dendritic spine generation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Conditioning, Psychological / physiology
  • Dendritic Spines / ultrastructure
  • Disks Large Homolog 4 Protein
  • Exploratory Behavior / physiology
  • Fear
  • Guanylate Kinases / metabolism
  • Hippocampus / cytology
  • Insulin Receptor Substrate Proteins / deficiency
  • Insulin Receptor Substrate Proteins / metabolism*
  • Maze Learning / physiology
  • Membrane Proteins / metabolism
  • Memory / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / genetics
  • Neurons / metabolism
  • Neurons / ultrastructure
  • Rotarod Performance Test / methods
  • Sequence Deletion / genetics

Substances

  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Insulin Receptor Substrate Proteins
  • Irs2 protein, mouse
  • Membrane Proteins
  • Guanylate Kinases