Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK.
Neuropsychopharmacology. 2012 Jan;37(2):364-77. doi: 10.1038/npp.2011.219. Epub 2011 Sep 28.
Administration of the DNA-alkylating agent methylazoxymethanol acetate (MAM) on embryonic day 17 (E17) produces behavioral and anatomical brain abnormalities, which model some aspects of schizophrenia. This has lead to the premise that MAM rats are a neurodevelopmental model for schizophrenia. However, the underlying molecular pathways affected in this model have not been elucidated. In this study, we investigated the molecular phenotype of adult MAM rats by focusing on the frontal cortex and hippocampal areas, as these are known to be affected in schizophrenia. Proteomic and metabonomic analyses showed that the MAM treatment on E17 resulted primarily in deficits in hippocampal glutamatergic neurotransmission, as seen in some schizophrenia patients. Most importantly, these results were consistent with our finding of functional deficits in glutamatergic neurotransmission, as identified using electrophysiological recordings. Thus, this study provides the first molecular evidence, combined with functional validation, that the MAM-E17 rat model reproduces hippocampal deficits relevant to the pathology of schizophrenia.
在胚胎期第 17 天（E17）给予 DNA 烷化剂甲基偶氮甲醇乙酸盐（MAM）的处理会导致行为和解剖学上的大脑异常，这些异常模拟了精神分裂症的某些方面。这导致了这样的前提，即 MAM 大鼠是精神分裂症的神经发育模型。然而，这种模型中受影响的潜在分子途径尚未阐明。在这项研究中，我们通过关注前额叶皮层和海马区域，研究了成年 MAM 大鼠的分子表型，因为已知这些区域在精神分裂症中受到影响。蛋白质组学和代谢组学分析表明，E17 时的 MAM 处理主要导致海马谷氨酸能神经传递的缺陷，如一些精神分裂症患者所见。最重要的是，这些结果与我们使用电生理记录确定的谷氨酸能神经传递功能缺陷的发现一致。因此，这项研究提供了第一个分子证据，结合功能验证，表明 MAM-E17 大鼠模型再现了与精神分裂症病理学相关的海马缺陷。
