Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia

Urs Meyer, Joram Feldon, Manfred Schedlowski, Kay Yan Benjamin Yee

Research output: Journal article publicationReview articleAcademic researchpeer-review

351 Citations (Scopus)

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 6 h post-injection, (ii) 12 h following prenatal PolyI:C challenge, the foetal levels of interleukin-1β 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.
Original languageEnglish
Pages (from-to)913-947
Number of pages35
JournalNeuroscience and Biobehavioral Reviews
Volume29
Issue number6
DOIs
Publication statusPublished - 16 Aug 2005
Externally publishedYes

Keywords

  • Animal model
  • Cytokines
  • Latent inhibition
  • Maternal infection
  • Polyriboinosinic-polyribocytidilic acid
  • Prepulse inhibition
  • Psychosis
  • Reversal learning
  • The partial reinforcement extinction effect
  • Working memory

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology
  • Cognitive Neuroscience
  • Behavioral Neuroscience

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