Search for proteins associated with schizophrenia in the brain and its therapeutic application

本研究旨在探讨N-甲基-D-天冬氨酸(NMDA)受体在精神分裂症阴性综合征的发病机制中的作用。转录因子是一种核蛋白，对特定的核心核苷酸序列具有高亲和力，调节RNA聚合酶II的活性，该聚合酶负责从细胞核中的基因组DNA形成mRNA。全身给药后，小鼠脑内转录因子激活蛋白-1(AP1)的DNA结合活性明显增强。在冷冻恒温器的帮助下制作冰冻的冠状切片，然后在双目显微镜下用干冰上的塑料毛细管冲出所需的区域。这种增强作用仅见于齿状颗粒细胞，而不存在于CA1和CA3锥体细胞。海马齿状回的增强作用是短暂的，给药后2 h达高峰，4 h内减弱，对NMDA通道阻滞剂的拮抗作用敏感。但在给药后4h，NMDA不能显著增强CA1和CA3锥体神经元中AP1DNA的结合。免疫组织化学分析显示，NMDA诱导c-jun和c-Fos蛋白在齿状回表达，但在CA1和CA3亚区不表达。此外，全身注射NMDA会导致小鼠出现各种异常行为，如咬尾巴2小时。这些结果表明，特定蛋白质从头合成的调节可能是导致精神分裂症等脑功能长期变化的机制之一。

The present study deals with modulation of gene transcription in the brain, in order to evaluate possible involvement of N-methyl-D-aspartate (NMDA) receptor in mechanisms underlying the crisis of negative syndromes of Schizophrenia. Transcription factors are nuclear proteins with high affinity for a particular core nucleotide sequence to modulate the activity of RNA polymerase II that is responsible for formation of mRNA from genomic DNA in the nucleus. The systemic administration of NMDA led to selective and drastic potentiation of DNA binding activity of the transcription factor activator protein-1 (AP1) in murine brain. Frozen coronal sections were made with the aid of a cryostat, followed by punching out of the desired regions by a plastic capillary on dry ice under a binocular microscope. The potentiation was only seen in the dentate granule cells, but not in the CA1 and CA3 pyramidal cells. The potentiation in the dentate gyrus was transient with a peak at 2 h after administration and a diminution within 4 h later, which occurred in a manner sensitive to antagonism by an NMDA channel blocker. However, NMDA failed to markedly potentiate AP1 DNA binding in the CA1 and CA3 pyramidal neurons up to 4 h after administration. Immunohistochemical analysis revealed that NMDA induced expression of both c-Jun and c-Fos proteins in the dentate gyrus, but not in the CA1 and CA3 subfields. Moreover, a systemic injection of NMDA resulted in a variety of abnormal behaviors, such as tail biting, in mice for 2 h. These results suggest that modulation of de novo synthesis of particular proteins may underlie mechanisms associated with long-lasting alterations of brain functions such as Schizophrenia.