title: Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia.
abstract: Epidemiological studies have indicated an association between maternal bacterial and viral infections during pregnancy and the higher incidence of schizophrenia in the resultant offspring post-puberty. One hypothesis asserts that the reported epidemiological link is mediated by prenatal activation of the foetal immune system in response to the elevation of maternal cytokine level due to infection. Here, we report that pregnant mouse dams receiving a single exposure to the cytokine-releasing agent, polyriboinosinic-polyribocytidilic acid (PolyI:C; at 2.5, 5.0, or 10.0 mg/kg) on gestation day 9 produced offspring that subsequently exhibited multiple schizophrenia-related behavioural deficits in adulthood, in comparison to offspring from vehicle injected or non-injected control dams. The efficacy of the PolyI:C challenge to induce cytokine responses in naïve non-pregnant adult female mice and in foetal brain tissue when injected to pregnant mice were further ascertained in separate subjects: (i) a dose-dependent elevation of interleukin-10 was detected in the adult female mice at 1 and 6h post-injection, (ii) 12 h following prenatal PolyI:C challenge, the foetal levels of interleukin-1beta were elevated. The spectrum of abnormalities included impairments in exploratory behaviour, prepulse inhibition, latent inhibition, the US-pre-exposure effect, spatial working memory; and enhancement in the locomotor response to systemic amphetamine (2.5 mg/kg, i.p.) as well as in discrimination reversal learning. The neuropsychological parallels between prenatal PolyI:C treatment in mice and psychosis in humans, demonstrated here, leads us to conclude that prenatal PolyI:C treatment represents one of the most powerful environmental-developmental models of schizophrenia to date. The uniqueness of this model lies in its epidemiological and immunological relevance. It is, sui generis, ideally suited for the investigation of the neuropsychoimmunological mechanisms implicated in the developmental aetiology and disease processes of schizophrenia.
authors.affiliation: Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology Zurich, Schorenstrasse 16, Schwerzenbach 8603, Switzerland.
authors.forename: Urs
authors.initials: U
authors.lastname: Meyer
authors.forename: Joram
authors.initials: J
authors.lastname: Feldon
authors.forename: Manfred
authors.initials: M
authors.lastname: Schedlowski
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Yee
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001923:Brain Chemistry; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D006801:Humans; D007266:Inhibition, Psychological; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology; D011119:Polynucleotides / Q000633:toxicity; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012022:Reflex, Acoustic / Q000502:physiology; D012559:Schizophrenia / Q000209:etiology / Q000276:immunology / Q000503:physiopathology; D012565:Schizophrenic Psychology
chemical_list: D016207:Cytokines; D011119:Polynucleotides; C049667:poly(rI).poly(dC)