Harris Laura W, Lockstone Helen E, Khaitovich Phillipp, Weickert Cynthia Shannon, Webster Maree J, Bahn Sabine
Institute of Biotechnology, University of Cambridge, Cambridge, UK.
BMC Med Genomics. 2009 May 20;2:28. doi: 10.1186/1755-8794-2-28.
Many critical maturational processes take place in the human brain during postnatal development. In particular, the prefrontal cortex does not reach maturation until late adolescence and this stage is associated with substantial white matter volume increases. Patients with schizophrenia and other major psychiatric disorders tend to first present with overt symptoms during late adolescence/early adulthood and it has been proposed that this developmental stage represents a "window of vulnerability".
In this study we used whole genome microarrays to measure gene expression in post mortem prefrontal cortex tissue from human individuals ranging in age from 0 to 49 years. To identify genes specifically altered in the late adolescent period, we applied a template matching procedure. Genes were identified which showed a significant correlation to a template showing a peak of expression between ages 15 and 25.
Approximately 2000 genes displayed an expression pattern that was significantly correlated (positively or negatively) with the template. In the majority of cases, these genes in fact reached a plateau during adolescence with only subtle changes thereafter. These include a number of genes previously associated with schizophrenia including the susceptibility gene neuregulin 1 (NRG1). Functional profiling revealed peak expression in late adolescence for genes associated with energy metabolism and protein and lipid synthesis, together with decreases for genes involved in glutamate and neuropeptide signalling and neuronal development/plasticity. Strikingly, eight myelin-related genes previously found decreased in schizophrenia brain tissue showed a peak in their expression levels in late adolescence, while the single myelin gene reported increased in patients with schizophrenia was decreased in late adolescence.
The observed changes imply that molecular mechanisms critical for adolescent brain development are disturbed in schizophrenia patients.
许多关键的成熟过程在人类大脑出生后的发育阶段发生。特别是,前额叶皮质直到青春期后期才成熟,这一阶段与大量白质体积增加有关。精神分裂症和其他主要精神疾病患者往往在青春期后期/成年早期首次出现明显症状,有人提出这个发育阶段代表一个“脆弱窗口”。
在本研究中,我们使用全基因组微阵列来测量年龄从0到49岁的人类个体死后前额叶皮质组织中的基因表达。为了鉴定在青春期后期特异性改变的基因,我们应用了模板匹配程序。鉴定出与在15至25岁之间显示表达峰值的模板具有显著相关性的基因。
大约2000个基因显示出与模板显著相关(正相关或负相关)的表达模式。在大多数情况下,这些基因实际上在青春期达到平台期,此后只有细微变化。这些基因包括一些先前与精神分裂症相关的基因,包括易感基因神经调节蛋白1(NRG1)。功能分析显示,与能量代谢以及蛋白质和脂质合成相关的基因在青春期后期表达达到峰值,而与谷氨酸和神经肽信号传导以及神经元发育/可塑性相关的基因表达下降。引人注目的是,先前在精神分裂症脑组织中发现表达降低的八个髓鞘相关基因在青春期后期表达水平达到峰值,而在精神分裂症患者中报道表达增加的单个髓鞘基因在青春期后期表达下降。
观察到的变化表明,精神分裂症患者中对青少年大脑发育至关重要的分子机制受到干扰。