title: Insulin receptor substrate 2 is a negative regulator of memory formation.
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.
authors: Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom.
authors: Elaine E
authors: EE
authors: Irvine
authors: Laura
authors: L
authors: Drinkwater
authors: Kasia
authors: K
authors: Radwanska
authors: Hind
authors: H
authors: Al-Qassab
authors: Mark A
authors: MA
authors: Smith
authors: Melissa
authors: M
authors: O'Brien
authors: Catherine
authors: C
authors: Kielar
authors: Agharul I
authors: AI
authors: Choudhury
authors: Stefan
authors: S
authors: Krauss
authors: Jonathan D
authors: JD
authors: Cooper
authors: Dominic J
authors: DJ
authors: Withers
authors: Karl Peter
authors: KP
authors: Giese
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