Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology.
Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology.
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DOI：
10.1016/j.biopsych.2010.09.022
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发表时间：
2010-12-15
影响因子：
10.6
通讯作者：
Pletnikov, Mikhail V.
中科院分区：
文献类型：
--
作者：
Abazyan, Bagrat;Nomura, Jun;Kannan, Geetha;Ishizuka, Koko;Tamashiro, Kellie L.;Nucifora, Frederick;Pogorelov, Vladimir;Ladenheim, Bruce;Yang, Chunxia;Krasnova, Irina N.;Cadet, Jean Lud;Pardo, Carlos;Mori, Susumu;Kamiya, Atsushi;Vogel, Michael W.;Sawa, Akira;Ross, Christopher A.;Pletnikov, Mikhail V.
基因-环境相互作用(GEI)参与了精神疾病的发病。我们评估了突变的人类精神分裂症中断-1(MhDISC1)与与精神分裂症和情绪障碍有关的母体免疫激活之间的相互作用。妊娠第9天分别给予生理盐水或多聚肌苷多胞苷(Poly I：C)处理。检测胎鼠和成年鼠脑内炎性细胞因子的水平，并检测新生小鼠大脑皮质中mhDISC1、内源性DISC1、LIS1、NDEL1、gp130、Grb2和GSK-3β的表达。对成年雄性小鼠的单胺类组织含量、脑体积异常、海马树突棘密度和小鼠行为的各个领域进行了评估。产前互动会产生焦虑、类似抑郁的反应，并改变社会行为模式。伴随这些行为的是HPA轴的反应性降低，海马5-羟色胺神经传递减弱，侧脑室扩大，杏仁核和中脑导水管周围灰质体积减少，海马颗粒细胞树突上的棘突密度减少。胎儿期的相互作用调节了胎儿大脑中炎性细胞因子的分泌、mhDISC1、内源性小鼠DISC1和GSK-3β的水平。只有当mhDISC1在整个生命周期中表达时，才能观察到GEI对行为的影响。产前免疫激活与mhDISC1相互作用，产生了在未经治疗的mhDISC1小鼠中未见的神经行为表型，并且类似于包括情绪障碍在内的主要精神疾病的方面。我们认为，我们的DISC1小鼠模型是一个有价值的系统，可以研究与精神疾病相关的GEI潜在的分子途径。
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. Pregnant mice were treated with saline or polyinosinic:polycytidylic acid (Poly I:C) at gestation day 9. Levels of inflammatory cytokines were measured in fetal and adult brains, expression of mhDISC1, endogenous DISC1, LIS1, NDEL1, gp130, Grb2, and GSK-3β 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. Prenatal interaction produced anxiety, depression-like responses, and altered pattern of social behavior. These behaviors were accompanied by decreased reactivity of the HPA axis, attenuated 5-HT 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 GSK-3β. The behavioral effects of GEI were observed only if mhDISC1 was expressed throughout the life span. 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, including mood disorders. We propose that our DISC1 mouse model is a valuable system to study the molecular pathways underlying GEI relevant to mental illnesses.
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影响因子：
3.1
作者：
Del-Ben CM;Graeff FG
通讯作者：
Graeff FG
影响因子：
2.7
作者：
Ayhan, Yavuz;Sawa, Akira;Ross, Christopher A.;Pletnikov, Mikhail V.
通讯作者：
Pletnikov, Mikhail V.
影响因子：
3.3
作者：
Gilmore, JH;Jarskog, LF;Vadlamudi, S
通讯作者：
Vadlamudi, S
影响因子：
3.1
作者：
Drevets, Wayne C.;Price, Joseph L.;Furey, Maura L.
通讯作者：
Furey, Maura L.
影响因子：
16.8
作者：
Beurel E;Michalek SM;Jope RS
通讯作者：
Jope RS