In-vivo administration of clozapine affects behaviour but does not reverse dendritic spine deficits in the 14-3-3 zeta KO mouse model of schizophrenia-like disorders

摘要

Clozapine is an atypical antipsychotic drug used in the treatment of schizophrenia, which has been shown to reverse behavioural and dendritic spine deficits in mice. It has recently been shown that deficiency of 14-3-3 zeta has an association with schizophrenia, and that a mouse model lacking this protein displays several schizophrenialike behavioural deficits. To test the effect of clozapine in this mouse model, 14-3-3 zeta KO mice were administered clozapine (5 mg/kg) for two weeks prior to being analysed in a test battery of cognition, anxiety, and despair (depression-like) behaviours. Following behavioural testing brain samples were collected for analysis of specific anatomical defects and dendritic spine formation. We found that clozapine reduced despair behaviour of 14-3-3 zeta KO mice in the forced swim test (FST) and altered the behaviour of wild types and 14-3-3 zeta KO mice in the Ymaze task. In contrast, clozapine had no effects on hippocampal laminar defects or decreased dendritic spine density observed in 14-3-3 zeta KO mice. Our results suggest that clozapine may have beneficial effects on clinical behaviours associated with deficiencies in the 14-3-3 zeta molecular pathway, despite having no effects on morphological defects. These findings may provide mechanistic insight to the action of this drug. (C) 2015 Elsevier Inc. All rights reserved.