Lai Wen-Sung, Xu Bin, Westphal Koen G C, Paterlini Marta, Olivier Berend, Pavlidis Paul, Karayiorgou Maria, Gogos Joseph A
Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16906-11. doi: 10.1073/pnas.0604994103. Epub 2006 Oct 31.
There is accumulating evidence that AKT signaling plays a role in the pathogenesis of schizophrenia. We asked whether Akt1 deficiency in mice results in structural and functional abnormalities in prefrontal cortex (PFC). Exploratory transcriptional profiling revealed concerted alterations in the expression of PFC genes controlling synaptic function, neuronal development, myelination, and actin polymerization, and follow-up ultrastructural analysis identified consistent changes in the dendritic architecture of pyramidal neurons. Behavioral analysis indicated that Akt1-mutant mice have normal acquisition of a PFC-dependent cognitive task but abnormal working memory retention under neurochemical challenge of three distinct neurotransmitter systems. Thus, Akt1 deficiency creates a context permissive for gene-gene and gene-environment interactions that modulate PFC functioning and contribute to the disease risk associated with this locus, the severity of the clinical syndrome, or both.
越来越多的证据表明，AKT信号传导在精神分裂症的发病机制中起作用。我们研究了小鼠中Akt1基因缺失是否会导致前额叶皮质（PFC）出现结构和功能异常。探索性转录谱分析揭示了控制突触功能、神经元发育、髓鞘形成和肌动蛋白聚合的PFC基因表达的协同改变，后续的超微结构分析确定了锥体神经元树突结构的一致变化。行为分析表明，Akt1基因敲除小鼠在依赖PFC的认知任务获取方面正常，但在三种不同神经递质系统的神经化学刺激下，工作记忆保持存在异常。因此，Akt1基因缺失为基因-基因和基因-环境相互作用创造了条件，这些相互作用调节PFC功能，并导致与该基因座相关的疾病风险、临床综合征的严重程度，或两者兼而有之。
