title: A "double hit" murine model for schizophrenia shows alterations in the structure and neurochemistry of the medial prefrontal cortex and the hippocampus.
abstract: Both alterations in neurodevelopment and aversive experiences during childhood and adolescence seem important risk factors for schizophrenia. Animal models reproducing these alterations mimic some of the symptoms, constituting a valid approach to study the etiopathology of this disorder. Among these models, the perinatal injection of N-methyl-d-aspartate receptor antagonists and the postweaning social isolation rearing are among the most widely used. Our aim is to combine them in a "double hit" model, which should produce a wider spectrum of alterations. Lister Hooded rats have been subjected to a single injection of MK-801 at postnatal day 7 and socially isolated from postweaning to adulthood. These animals presented increased body weight gain and volume reductions in their medial prefrontal cortex (mPFC) and hippocampus. They also showed an increased number of activated pyramidal neurons and alterations in the numbers of parvalbumin and calbindin expressing interneurons in the mPFC. The expressions of the polysialylated form of the neural cell adhesion molecule and GAD67 are decreased in the mPFC. The mRNA level of calbindin was decreased, while that of calretinin was increased in the mPFC. The mRNA level of ERbB4, a gene associated to schizophrenia, was also altered in this region. All these structural and neurochemical alterations, specially in cortical inhibitory circuits, are similar to those found in schizophrenic patients and are more numerous than in each of the single models. Consequently, the present "double hit" model may be a better tool to study the neurobiological basis of schizophrenia and to explore new therapeutic approaches.
authors.affiliation: Neurobiology Unit and Program in Basic and Applied Neurosciences, Cell Biology Dpt., Universitat de València, Spain; Genetics Dpt., Universitat de València, Spain; CIBERSAM, Spanish National Network for Research in Mental Health, Spain; Fundación Investigación Hospital Clínico de Valencia, INCLIVA, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Gilabert-Juan
authors.forename: Maria
authors.initials: M
authors.lastname: Belles
authors.forename: Ana Rosa
authors.initials: AR
authors.lastname: Saez
authors.forename: Hector
authors.initials: H
authors.lastname: Carceller
authors.forename: Sara
authors.initials: S
authors.lastname: Zamarbide-Fores
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Moltó
authors.forename: Juan
authors.initials: J
authors.lastname: Nacher
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology*; D011247:Pregnancy; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D012559:Schizophrenia / Q000209:etiology / Q000473:pathology*; D012934:Social Isolation
chemical_list: D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D016760:Proto-Oncogene Proteins c-fos; D016291:Dizocilpine Maleate
keywords: Adult neurogenesis; Animal model; Inhibitory neurotransmission; Interneuron; Schizophrenia