clozapine and difopein

The 14-3-3 family of proteins is implicated in the regulation of several key neuronal processes. Previous human and animal studies suggested an association between 14-3-3 dysregulation and schizophrenia.. We characterized behavioral and functional changes in transgenic mice that express an isoform-independent 14-3-3 inhibitor peptide in the brain.. We recently showed that 14-3-3 functional knockout mice (FKO) exhibit impairments in associative learning and memory. We report here that these 14-3-3 FKO mice display other behavioral deficits that correspond to the core symptoms of schizophrenia. These behavioral deficits may be attributed to alterations in multiple neurotransmission systems in the 14-3-3 FKO mice. In particular, inhibition of 14-3-3 proteins results in a reduction of dendritic complexity and spine density in forebrain excitatory neurons, which may underlie the altered synaptic connectivity in the prefrontal cortical synapse of the 14-3-3 FKO mice. At the molecular level, this dendritic spine defect may stem from dysregulated actin dynamics secondary to a disruption of the 14-3-3-dependent regulation of phosphorylated cofilin.. Collectively, our data provide a link between 14-3-3 dysfunction, synaptic alterations, and schizophrenia-associated behavioral deficits.

Topics: 14-3-3 Proteins; Animals; Antipsychotic Agents; Behavior, Animal; Catenins; Cerebral Cortex; Clozapine; Cofilin 1; Delta Catenin; Dendrites; Disease Models, Animal; Dopamine; Haloperidol; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Prepulse Inhibition; Proteins; Receptors, Dopamine; Schizophrenia; Schizophrenic Psychology; Synaptic Transmission