title: In-vivo administration of clozapine affects behaviour but does not reverse dendritic spine deficits in the 14-3-3ζ KO mouse model of schizophrenia-like disorders.
abstract: 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 14-3-3ζ has an association with schizophrenia, and that a mouse model lacking this protein displays several schizophrenia-like behavioural deficits. To test the effect of clozapine in this mouse model, 14-3-3ζ KO mice were administered clozapine (5mg/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 14-3-3ζ KO mice in the forced swim test (FST) and altered the behaviour of wild types and 14-3-3ζ KO mice in the Y-maze task. In contrast, clozapine had no effects on hippocampal laminar defects or decreased dendritic spine density observed in 14-3-3ζ KO mice. Our results suggest that clozapine may have beneficial effects on clinical behaviours associated with deficiencies in the 14-3-3ζ molecular pathway, despite having no effects on morphological defects. These findings may provide mechanistic insight to the action of this drug.
authors.affiliation: Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Jaehne
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Hayley
authors.initials: H
authors.lastname: Ramshaw
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Xu
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Eiman
authors.initials: E
authors.lastname: Saleh
authors.affiliation: Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Clark
authors.affiliation: Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Klaus Oliver
authors.initials: KO
authors.lastname: Schubert
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Angel
authors.initials: A
authors.lastname: Lopez
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Quenten
authors.initials: Q
authors.lastname: Schwarz
authors.affiliation: Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia. Electronic address: Bernhard.Baune@Adelaide.edu.au.
authors.forename: Bernhard T
authors.initials: BT
authors.lastname: Baune
mesh_terms: D048948:14-3-3 Proteins / Q000187:drug effects* / Q000235:genetics*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000473:pathology; D003024:Clozapine / Q000494:pharmacology*; D003071:Cognition; D049229:Dendritic Spines / Q000187:drug effects*; D003863:Depression / Q000523:psychology; D004644:Emotions; D051379:Mice; D018345:Mice, Knockout; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D012565:Schizophrenic Psychology
chemical_list: D048948:14-3-3 Proteins; D014150:Antipsychotic Agents; C499130:Sfn protein, mouse; D003024:Clozapine
keywords: 14-3-3ζ; Anxiety; Clozapine; Cognition; Dendritic spines; Depression