LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage.
LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage.
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DOI：
10.1038/tp.2015.33
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发表时间：
2015-04-07
影响因子：
6.8
通讯作者：
Chun J
中科院分区：
文献类型：
--
作者：
Mirendil H;Thomas EA;De Loera C;Okada K;Inomata Y;Chun J
遗传、环境和神经发育因素被认为是精神分裂症等神经精神障碍发病的基础。这些风险因素如何共同作用于病理尚不清楚。在这里，我们提出了一种产前脑出血的小鼠模型--一种已确定的精神分裂症的危险因素--使用血清暴露范式。该模型在成年女性中表现出行为、神经化学和精神分裂症相关基因表达的变化。除了黑质和腹侧被盖区酪氨酸羟基酶阳性的多巴胺能细胞增加，前额叶皮质小白蛋白阳性细胞减少外，安非他明诱导的运动、脉冲前抑制、触觉和社会相互作用的行为改变也被诱导。溶血磷脂酸(LPA)是血清中的一种脂质成分，被认为是血清诱发精神分裂症样后遗症的关键分子启动剂。仅产前暴露于LPA就可以出现许多在血清模型中看到的精神分裂症样变化，而用LPA受体亚型LPA1的拮抗剂预处理可以防止许多行为和神经化学变化。此外，产前血清和LPA暴露都改变了许多与精神分裂症相关的基因和途径的表达，包括GRIN2B、SLC17a7和Grid1的表达。这些发现表明，与胎儿脑出血相关的LPA受体信号异常可能有助于某些神经精神障碍的发展。
Genetic, environmental and neurodevelopmental factors are thought to underlie the onset of neuropsychiatric disorders such as schizophrenia. How these risk factors collectively contribute to pathology is unclear. Here, we present a mouse model of prenatal intracerebral hemorrhage—an identified risk factor for schizophrenia—using a serum-exposure paradigm. This model exhibits behavioral, neurochemical and schizophrenia-related gene expression alterations in adult females. Behavioral alterations in amphetamine-induced locomotion, prepulse inhibition, thigmotaxis and social interaction—in addition to increases in tyrosine hydroxylase-positive dopaminergic cells in the substantia nigra and ventral tegmental area and decreases in parvalbumin-positive cells in the prefrontal cortex—were induced upon prenatal serum exposure. Lysophosphatidic acid (LPA), a lipid component of serum, was identified as a key molecular initiator of schizophrenia-like sequelae induced by serum. Prenatal exposure to LPA alone phenocopied many of the schizophrenia-like alterations seen in the serum model, whereas pretreatment with an antagonist against the LPA receptor subtype LPA1 prevented many of the behavioral and neurochemical alterations. In addition, both prenatal serum and LPA exposure altered the expression of many genes and pathways related to schizophrenia, including the expression of Grin2b, Slc17a7 and Grid1. These findings demonstrate that aberrant LPA receptor signaling associated with fetal brain hemorrhage may contribute to the development of some neuropsychiatric disorders.
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DOI：
10.1073/pnas.1106129108
发表时间：
2011-09-13
影响因子：
11.1
作者：
Herr, Keira Joann;Herr, Deron R.;Chun, Jerold
通讯作者：
Chun, Jerold
影响因子：
15.9
作者：
Cruz-Orengo, Lillian;Daniels, Brian P.;Klein, Robyn S.
通讯作者：
Klein, Robyn S.
影响因子：
30.8
作者：
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通讯作者：
Bertram, Lars
DOI：
10.1111/j.1749-6632.2002.tb04210.x
发表时间：
2002-01-01
期刊：
NEUROENDOCRINE IMMUNE BASIS OF THE RHEUMATIC DISEASES II, PROCEEDINGS
影响因子：
--
作者：
Cutolo, M;Seriolo, B;Sulli, A
通讯作者：
Sulli, A
影响因子：
4.5
作者：
Byrne, Majella;Agerbo, Esben;Mortensen, Preben Bo
通讯作者：
Mortensen, Preben Bo