Forebrain-specific expression of monoamine oxidase a reduces neurotransmitter levels, restores the brain structure, and rescues aggressive behavior in monoamine oxidase A-deficient mice
Forebrain-specific expression of monoamine oxidase a reduces neurotransmitter levels, restores the brain structure, and rescues aggressive behavior in monoamine oxidase A-deficient mice
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DOI：
10.1074/jbc.m609830200
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发表时间：
2007-01-05
影响因子：
4.8
通讯作者：
Shih, Jean Chen
中科院分区：
文献类型：
--
作者：
Chen, Kevin;Cases, Olivier;Shih, Jean Chen
先前的研究已经证实，单胺氧化酶（MAO） A的表达缺失会导致神经化学、形态学和行为特异性表型，包括血清素（5-HT）、去甲肾上腺素和多巴胺水平升高，小鼠体感觉皮层桶状场结构丧失，并与成人攻击性增加有关。利用钙依赖性激酶II α (CaMKII α)启动子，从MAO A敲除（KO）小鼠中产生前脑特异性MAO A转基因小鼠。分别用基因组DNA PCR、mRNA逆转录PCR和Western blot验证了人MAO A基因的存在和表达。在前脑转基因小鼠的额叶皮质、纹状体和海马中发现了显著的MAO A催化活性、5-羟色胺的放射自显影标记和MAO A的免疫细胞化学，但在小脑中没有发现。此外，与MAO A KO小鼠相比，转基因小鼠在前脑区域发现5-羟色胺、去甲肾上腺素和DA水平较低，而在小脑区域发现MAO A代谢物5-羟基- dole乙酸水平较高。这些结果表明MAO A在转基因小鼠的前脑区域特异性表达。这种前脑特异性差异表达导致侵略性表型的消除。此外，MAO A KO小鼠体感觉皮质桶野结构的紊乱得到恢复，并在形态上与野生型相似。因此，MAO A KO小鼠的前脑缺乏MAO A可能是其表型的基础。
Previous studies have established that abrogation of monoamine oxidase (MAO) A expression leads to a neurochemical, morphological, and behavioral specific phenotype with increased levels of serotonin (5-HT), norepinephrine, and dopamine, loss of barrel field structure in mouse somatosensory cortex, and an association with increased aggression in adults. Forebrain-specific MAO A transgenic mice were generated from MAO A knock-out (KO) mice by using the promoter of calcium-dependent kinase II alpha (CaMKII alpha). The presence of human MAO A transgene and its expression were verified by PCR of genomic DNA and reverse transcription-PCR of mRNA and Western blot, respectively. Significant MAO A catalytic activity, autoradiographic labeling of 5-HT, and immunocytochemistry of MAO A were found in the frontal cortex, striatum, and hippocampus but not in the cerebellum of the forebrain transgenic mice. Also, compared with MAO A KO mice, lower levels of 5-HT, norepinephrine, and DA and higher levels of MAO A metabolite 5-hydroxyin-doleacetic acid were found in the forebrain regions but not in the cerebellum of the transgenic mice. These results suggest that MAO A is specifically expressed in the forebrain regions of transgenic mice. This forebrain-specific differential expression resulted in abrogation of the aggressive phenotype. Furthermore, the disorganization of the somatosensory cortex barrel field structure associated with MAO A KO mice was restored and became morphologically similar to wild type. Thus, the lack of MAO A in the forebrain of MAO A KO mice may underlie their phenotypes.