Canonical Wnt signaling is necessary for object recognition memory consolidation

J Neurosci. 2013 Jul 31;33(31):12619-26. doi: 10.1523/JNEUROSCI.0659-13.2013.

Abstract

Wnt signaling has emerged as a potent regulator of hippocampal synaptic function, although no evidence yet supports a critical role for Wnt signaling in hippocampal memory. Here, we sought to determine whether canonical β-catenin-dependent Wnt signaling is necessary for hippocampal memory consolidation. Immediately after training in a hippocampal-dependent object recognition task, mice received a dorsal hippocampal (DH) infusion of vehicle or the canonical Wnt antagonist Dickkopf-1 (Dkk-1; 50, 100, or 200 ng/hemisphere). Twenty-four hours later, mice receiving vehicle remembered the familiar object explored during training. However, mice receiving Dkk-1 exhibited no memory for the training object, indicating that object recognition memory consolidation is dependent on canonical Wnt signaling. To determine how Dkk-1 affects canonical Wnt signaling, mice were infused with vehicle or 50 ng/hemisphere Dkk-1 and protein levels of Wnt-related proteins (Dkk-1, GSK3β, β-catenin, TCF1, LEF1, Cyclin D1, c-myc, Wnt7a, Wnt1, and PSD95) were measured in the dorsal hippocampus 5 min or 4 h later. Dkk-1 produced a rapid increase in Dkk-1 protein levels and a decrease in phosphorylated GSK3β levels, followed by a decrease in β-catenin, TCF1, LEF1, Cyclin D1, c-myc, Wnt7a, and PSD95 protein levels 4 h later. These data suggest that alterations in Wnt/GSK3β/β-catenin signaling may underlie the memory impairments induced by Dkk-1. In a subsequent experiment, object training alone rapidly increased DH GSK3β phosphorylation and levels of β-catenin and Cyclin D1. These data suggest that canonical Wnt signaling is regulated by object learning and is necessary for hippocampal memory consolidation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclin D1 / metabolism
  • Disks Large Homolog 4 Protein
  • Dose-Response Relationship, Drug
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology*
  • Functional Laterality / drug effects
  • Functional Laterality / physiology
  • Gene Expression Regulation / drug effects
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Guanylate Kinases / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Male
  • Membrane Proteins / metabolism
  • Memory Disorders / chemically induced
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation / drug effects
  • Recognition, Psychology / drug effects
  • Recognition, Psychology / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Statistics, Nonparametric
  • Wnt Proteins / antagonists & inhibitors
  • Wnt Proteins / metabolism*
  • beta Catenin / metabolism

Substances

  • Disks Large Homolog 4 Protein
  • Dkk1 protein, mouse
  • Dlg4 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Wnt Proteins
  • beta Catenin
  • Cyclin D1
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3
  • Guanylate Kinases