Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders.
Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders.
复制标题
DOI：
10.1186/1756-6606-1-6
复制
发表时间：
2008-09-10
期刊：
影响因子：
3.6
通讯作者：
Miyakawa, Tsuyoshi
中科院分区：
文献类型：
--
作者：
Yamasaki, Nobuyuki;Maekawa, Motoko;Kobayashi, Katsunori;Kajii, Yasushi;Maeda, Jun;Soma, Miho;Takao, Keizo;Tanda, Koichi;Ohira, Koji;Toyama, Keiko;Kanzaki, Kouji;Fukunaga, Kohji;Sudo, Yusuke;Ichinose, Hiroshi;Ikeda, Masashi;Iwata, Nakao;Ozaki, Norio;Suzuki, Hidenori;Higuchi, Makoto;Suhara, Tetsuya;Yuasa, Shigeki;Miyakawa, Tsuyoshi
目前的临床诊断方法阻碍了阐明精神疾病潜在的神经和遗传因素。临床内表型的鉴定和研究可能是一种解决方案，但在人类受试者中代表了相当大的挑战。在这里，我们报告说，杂合子的α-异构体的钙/钙调蛋白依赖性蛋白激酶II（α-CaMKII +/-）的无效突变的小鼠有深刻的失调行为和受损的神经元发育的齿状回（DG）。行为异常包括严重的工作记忆缺陷和夸张的亚昼夜节律，这与精神分裂症，双相情感障碍和其他精神疾病的症状相似。对这些突变体海马的转录组分析显示，超过2000个基因的表达水平发生了显着变化。引人注目的是，在20个下调最多的基因中，5个在DG中具有高度选择性表达。而BrdU掺入突变小鼠DG中的细胞增加了50%以上，DG中成熟神经元的数量急剧减少。突变体中DG神经元的形态和生理特征与正常啮齿动物中未成熟的DG神经元的形态和生理特征惊人地相似。此外，c-Fos的表达在DG电击后几乎完全和选择性地取消在突变体。使用突变小鼠中差异表达的10个基因对人类死后大脑进行统计聚类，将个体分为两组，其中一组包含18名精神分裂症患者中的16名。近一半的差异表达的探针在精神分裂症丰富的集群编码的基因，参与神经发生或神经元迁移/成熟，包括钙结合蛋白，成熟DG神经元的标志物。基于这些结果，我们提出，一个“不成熟的DG”在成年期可能会引起行为的改变，并作为一个有前途的候选内表型的精神分裂症和其他人类精神疾病。
Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders.
登录
查看更多内容
影响因子：
64.8
作者：
Arron, Joseph R.;Winslow, Monte M.;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
DOI：
10.1016/s0169-328x(99)00131-x
发表时间：
1999-06-18
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Bayer, KU;Löhler, J;Harbers, K
通讯作者：
Harbers, K
影响因子：
64.8
作者：
Frankland, PW;O'Brien, C;Silva, AJ
通讯作者：
Silva, AJ
影响因子：
56.9
作者：
Frankland, PW;Bontempi, B;Silva, AJ
通讯作者：
Silva, AJ
DOI：
10.1073/pnas.1432927100
发表时间：
2003-07-22
影响因子：
11.1
作者：
Gerber, DJ;Hall, D;Tonegawa, S
通讯作者：
Tonegawa, S