Prenatal treatment with methylazoxymethanol acetate as a neurodevelopmental disruption model of schizophrenia in mice
Prenatal treatment with methylazoxymethanol acetate as a neurodevelopmental disruption model of schizophrenia in mice
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用醋酸甲基偶氮甲醇作为小鼠精神分裂症神经发育障碍模型的产前治疗
DOI：
10.1016/j.neuropharm.2019.02.034
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发表时间：
2019
影响因子：
4.7
通讯作者：
Tan-No Koichi
中科院分区：
文献类型：
--
作者：
Takahashi Kohei;Nakagawasai Osamu;Sakuma Wakana;Nemoto Wataru;Odaira Takayo;Lin Jia-Rong;Onogi Hiroshi;Srivastava Lalit K.;Tan-No Koichi
甲基甲氧基甲醇（MAM）治疗妊娠第17天的大鼠已被证明是一种有价值的精神分裂症发育动物模型。然而，该模型仍有待在小鼠身上建立。在本研究中，我们检测了mam治疗小鼠后代的行为、细胞结构和神经化学变化，并验证了模型的外观、结构和预测有效性。我们发现，与在第15、16或17岁时单次注射MAM相比，从第15至17岁每天注射MAM会导致青春期后后代惊吓前抑制（PPI）的缺陷。此外，我们观察到GD15-17 MAM后代在工作记忆和社会互动方面的行为缺陷，以及NMDA拮抗剂MK-801诱导的运动活动增加。这些动物还表现出前额叶皮质（PFC）和海马的体积减少，海马的神经解剖学改变，如不连续和异位，内侧PFC的DA水平和DOPAC/DA比值增加。非典型抗精神病药物氯氮平、利培酮和阿立哌唑，而非典型药物氟哌啶醇，可以逆转mam治疗的母鼠后代的PPI缺陷和社交退缩。相比之下，mk -801诱导的MAM小鼠的过度活跃被两种典型或非典型抗精神病药物逆转。综上所述，MAM治疗妊娠期15-17的妊娠小鼠为研究精神分裂症发病机制的神经生物学机制提供了新的途径。
Methylazoxymethanol (MAM)-treated pregnant rat at gestation day (GD) 17 has been shown to be a valuable developmental animal model for schizophrenia. Yet, this model remains to be established in mice. In the present study, we examined behavioral, cytoarchitectural, and neurochemical changes in the offspring of MAM-treated mice and validated the model's face, construct and predictive validities. We found that in contrast to a single injection of MAM to dams at GD 15, 16 or 17, its daily administration from GD 15 to 17 led to deficits in prepulse inhibition (PPI) of startle in the post-pubertal offspring. In addition, we observed behavioral deficits in working memory and social interactions, as well as an increase in locomotor activity induced by the NMDA antagonist MK-801 in GD15-17 MAM offspring. These animals also showed a reduction in the volume of the prefrontal cortex (PFC) and hippocampus, neuroanatomical changes such as discontinuities and heterotopias in the hippocampus, and an increase of DA level and DOPAC/DA ratio in the medial PFC. Atypical antipsychotic drugs clozapine, risperidone, and aripiprazole, but not the typical drug haloperidol, reversed the deficit in PPI and social withdrawal in the offspring of MAM-treated dams. In contrast, MK-801-induced hyperactivity in MAM mice was reversed by both and typical or atypical antipsychotic drugs. Taken together, the treatment of pregnant mice with MAM during GD 15–17 offers a new approach to study neurobiological mechanisms involved in the pathogenesis of schizophrenia.
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影响因子：
2.9
作者：
S. Stahl;A. Malla;J. Newcomer;S. Potkin;P. Weiden;Philip D. Harvey;A. Loebel;E. Watsky;C. Siu;S. Romano
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影响因子：
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作者：
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通讯作者：
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影响因子：
10.6
作者：
J. Waddington;A. Lane;C. Larkin;E. O'callaghan
通讯作者：
E. O'callaghan
影响因子：
3.8
作者：
HALLMAN, H;JONSSON, G
通讯作者：
JONSSON, G
影响因子：
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作者：
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通讯作者：
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