Deletion of the neuron-specific protein delta-catenin leads to severe cognitive and synaptic dysfunction.
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.
Israely
Inbal
I
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
Costa
Rui M
RM
Xie
Cui Wei
CW
Silva
Alcino J
AJ
Kosik
Kenneth S
KS
Liu
Xin
X
D000704:Analysis of Variance; D000818:Animals; D051186:Armadillo Domain Proteins; D015820:Cadherins / Q000378:metabolism; D051177:Catenins; D015815:Cell Adhesion Molecules; D003072:Cognition Disorders / Q000209:etiology*; D003213:Conditioning, Psychological / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000235:genetics; D000076122:Disks Large Homolog 4 Protein; D004594:Electrophysiology; D005239:Fear / Q000502:physiology; D051528:Guanylate Kinases; D006624:Hippocampus / Q000503:physiopathology*; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000209:etiology*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D010750:Phosphoproteins; D011597:Psychomotor Performance / Q000502:physiology; D013569:Synapses / Q000235:genetics / Q000378:metabolism*; D000095002:Delta Catenin
D051186:Armadillo Domain Proteins; D015820:Cadherins; D051177:Catenins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; C033652:postsynaptic density proteins; D051528:Guanylate Kinases; D000095002:Delta Catenin