Prenatal Interaction of Mutant DISC1 and Immune Activation Produces Adult Psychopathology

被引：195

作者：

Abazyan, Bagrat ^{[1
]}

Nomura, Jun ^{[1
]}

Kannan, Geetha ^{[1
,7
]}

Ishizuka, Koko ^{[8
]}

Tamashiro, Kellie L.

Nucifora, Frederick ^{[1
]}

Pogorelov, Vladimir ^{[1
]}

Ladenheim, Bruce ^{[10
]}

Yang, Chunxia ^{[1
]}

Krasnova, Irina N. ^{[10
]}

Cadet, Jean Lud ^{[10
]}

Pardo, Carlos ^{[2
]}

Mori, Susumu ^{[2
,4
]}

Kamiya, Atsushi ^{[8
]}

Vogel, Michael W. ^{[11
]}

Sawa, Akira ^{[3
,7
,8
,9
]}

Ross, Christopher A. ^{[1
,2
,3
,5
,7
]}

Pletnikov, Mikhail V. ^{[1
,3
,6
,7
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Div Neurobiol, Baltimore, MD 21287 USA

[2] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA

[3] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21287 USA

[4] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21287 USA

[5] Johns Hopkins Univ, Sch Med, Dept Pharmacol, Baltimore, MD 21287 USA

[6] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21287 USA

[7] Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Baltimore, MD 21287 USA

[8] Johns Hopkins Univ, Sch Med, Program Mol Psychiat, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA

[9] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21287 USA

[10] Natl Inst Drug Abuse, Mol Neuropsychiat Branch, NIH, US Dept HHS, Baltimore, MD USA

[11] Univ Maryland, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA

来源：

BIOLOGICAL PSYCHIATRY | 2010年 / 68卷 / 12期

基金：

美国国家卫生研究院;

关键词：

DISC1; gene-environment interactions; mood disorders; mouse models; schizophrenia; Tet-off system; DENDRITIC SPINE DENSITY; GENE-ENVIRONMENT INTERACTIONS; BIPOLAR DISORDER; MOOD DISORDERS; BEHAVIORAL PHENOTYPES; INDUCIBLE EXPRESSION; SCHIZOPHRENIA RISK; PREFRONTAL CORTEX; GENOMIC STRUCTURE; INFECTION;

D O I：

10.1016/j.biopsych.2010.09.022

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：1172 / 1181

页数：10

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