Deletion of the neuron-specific protein delta-catenin leads to severe cognitive and synaptic dysfunction

Curr Biol. 2004 Sep 21;14(18):1657-63. doi: 10.1016/j.cub.2004.08.065.

Abstract

Delta-catenin (delta-catenin) is a neuron-specific catenin, which has been implicated in adhesion and dendritic branching. Moreover, deletions of delta-catenin correlate with the severity of mental retardation in Cri-du-Chat syndrome (CDCS), which may account for 1% of all mentally retarded individuals. Interestingly, delta-catenin was first identified through its interaction with Presenilin-1 (PS1), the molecule most frequently mutated in familial Alzheimer's Disease (FAD). We investigated whether deletion of delta-catenin would be sufficient to cause cognitive dysfunction by generating mice with a targeted mutation of the delta-catenin gene (delta-cat(-/-)). We observed that delta-cat(-/-) animals are viable and have severe impairments in cognitive function. Furthermore, mutant mice display a range of abnormalities in hippocampal short-term and long-term synaptic plasticity. Also, N-cadherin and PSD-95, two proteins that interact with delta-catenin, are significantly reduced in mutant mice. These deficits are severe but specific because delta-cat(-/-) mice display a variety of normal behaviors, exhibit normal baseline synaptic transmission, and have normal levels of the synaptic adherens proteins E-cadherin and beta-catenin. These data reveal a critical role for delta-catenin in brain function and may have important implications for understanding mental retardation syndromes such as Cri-du-Chat and neurodegenerative disorders, such as Alzheimer's disease, that are characterized by cognitive decline.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Animals
  • Armadillo Domain Proteins
  • Cadherins / metabolism
  • Catenins
  • Cell Adhesion Molecules
  • Cognition Disorders / etiology*
  • Conditioning, Psychological / physiology
  • Cytoskeletal Proteins / deficiency*
  • Cytoskeletal Proteins / genetics
  • Disks Large Homolog 4 Protein
  • Electrophysiology
  • Fear / physiology
  • Guanylate Kinases
  • Hippocampus / physiopathology*
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins
  • Maze Learning / physiology
  • Membrane Proteins
  • Mice
  • Mice, Mutant Strains
  • Mutation / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurodegenerative Diseases / etiology*
  • Neuronal Plasticity / physiology
  • Neurons / metabolism*
  • Phosphoproteins
  • Psychomotor Performance / physiology
  • Synapses / genetics
  • Synapses / metabolism*

Substances

  • Armadillo Domain Proteins
  • Cadherins
  • Catenins
  • Cell Adhesion Molecules
  • Cytoskeletal Proteins
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Phosphoproteins
  • delta catenin
  • postsynaptic density proteins
  • Guanylate Kinases