title: Effects of antipsychotics on the behavioral deficits in human dominant-negative DISC1 transgenic mice with neonatal polyI:C treatment.
abstract: Interactions of environmental and genetic factors may play a role in the pathoetiology of schizophrenia. We have recently developed a novel animal model of mental disorders such as schizophrenia by inducing abnormal immune response during the perinatal period in mice with overexpression of the human dominant-negative form of disrupted-in-schizophrenia 1 (DN-DISC1). In the present study, we investigated the effects of antipsychotics on the behavioral deficits in this animal model for mental disorders with gene-environment interaction. Neonatal DN-DISC1 transgenic (DN-DISC1 tg) mice were repeatedly injected with polyriboinosinic-polyribocytidylic acid (polyI:C) for 5 days from postnatal days 2 to 6. The behavioral analyses were performed in adulthood. Clozapine (3mg/kg) or haloperidol (1mg/kg) was administered orally once a day from 1 week before starting a series of behavioral experiments and continued until the end of the study. Cognitive impairment in polyI:C-treated DN-DISC1 tg mice was improved by repeated administration of clozapine while haloperidol had no effect. Both antipsychotics suppressed the augmentation of MK-801-induced hyperactivity in the model mice. Neither clozapine nor haloperidol ameliorated the impairments of social behaviors in polyI:C-treated DN-DISC1 tg mice. These results suggest that the polyI:C-treated DN-DISC tg mice are quite unique as an animal model for mental disorders. Furthermore, this mouse model may be useful for the screening of potential antipsychotic compounds that could be more effective than clozapine in ameliorating negative symptoms and cognitive impairment in schizophrenia.
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Nagai
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitahara
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ibi
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001526:Behavioral Symptoms / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity; D059647:Gene-Environment Interaction; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011070:Poly I-C / Q000627:therapeutic use*
chemical_list: D014150:Antipsychotic Agents; C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins; D016291:Dizocilpine Maleate; D011070:Poly I-C