Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology

Bagrat Abazyan, Jun Nomura, Geetha Kannan, Koko Ishizuka, Kellie L. Tamashiro, Frederick Nucifora, Vladimir Pogorelov, Bruce Ladenheim, Chunxia Yang, Irina N. Krasnova, Jean Lud Cadet, Carlos Pardo, Susumu Mori, Atsushi Kamiya, Michael W. Vogel, Akira Sawa, Christopher A. Ross, Mikhail V. Pletnikov

Research output: Contribution to journalArticle

Abstract

Background Gene-environment interactions (GEI) are involved in the pathogenesis of mental diseases. We evaluated interaction between mutant human disrupted-in-schizophrenia 1 (mhDISC1) and maternal immune activation implicated in schizophrenia and mood disorders. Methods Pregnant mice were treated with saline or polyinosinic:polycytidylic acid at gestation day 9. Levels of inflammatory cytokines were measured in fetal and adult brains; expression of mhDISC1, endogenous DISC1, lissencephaly type 1, nuclear distribution protein nudE-like 1, glycoprotein 130, growth factor receptor-bound protein 2, and glycogen synthase kinase-3beta were assessed in cortical samples of newborn mice. Tissue content of monoamines, volumetric brain abnormalities, dendritic spine density in the hippocampus, and various domains of the mouse behavior repertoire were evaluated in adult male mice. Results Prenatal interaction produced anxiety, depression-like responses, and altered social behavior that were accompanied by decreased reactivity of the hypothalamic-pituitary-adrenal axis, attenuated serotonin neurotransmission in the hippocampus, reduced enlargement of lateral ventricles, decreased volumes of amygdala and periaqueductal gray matter and density of spines on dendrites of granule cells of the hippocampus. Prenatal interaction modulated secretion of inflammatory cytokines in fetal brains, levels of mhDISC1, endogenous mouse DISC1, and glycogen synthase kinase-3beta. The behavioral effects of GEI were observed only if mhDISC1 was expressed throughout the life span. Conclusions Prenatal immune activation interacted with mhDISC1 to produce the neurobehavioral phenotypes that were not seen in untreated mhDISC1 mice and that resemble aspects of major mental illnesses. Our DISC1 mouse model is a valuable system to study GEI relevant to mental illnesses.

Original languageEnglish (US)
Pages (from-to)1172-1181
Number of pages10
JournalBiological psychiatry
Volume68
Issue number12
DOIs
StatePublished - Dec 15 2010

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Keywords

  • DISC1
  • Tet-off system
  • gene-environment interactions
  • mood disorders
  • mouse models
  • schizophrenia

ASJC Scopus subject areas

  • Biological Psychiatry

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