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

Delta-catenin (8-catenin) is a neuron-specific catenin, which has been implicated in adhesion and dendritic branching (1, 2]. Moreover, deletions of 8-catenin correlate with the severity of mental retardation in Cridu-Chat syndrome (CDCS), which may account for 1% of all mentally retarded individuals [3]. Interestingly, delta-catenin was first identified through its interaction with Presenilin-1 (PS1), the molecule most frequently mutated in familial Alzheimer's Disease (FAD) [4]. We investigated whether deletion of 8-catenin would be sufficient to cause cognitive dysfunction by generating mice with a targeted mutation of the 8-catenin gene (delta-cat(-/-)). We observed that 8-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 8-catenin [1, 5], are significantly reduced in mutant mice. These deficits are severe but specific because (5-cat-1- 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 8-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.