Lowe Xiu R, Lu Xiaochen, Marchetti Francesco, Wyrobek Andrew J
Life Science, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
Brain Res. 2007 Oct 12;1174:7-17. doi: 10.1016/j.brainres.2007.07.039. Epub 2007 Aug 2.
The glutamatergic system has been implicated in neuropsychiatric disorders, such as schizophrenia, bipolar disorder and Alzheimer's disease, which also have a high prevalence of metabolic syndrome. Treatment with ketamine, a non-competitive glutamate N-methyl-d-aspartic acid (NMDA) receptor antagonist, is known to have paradoxical effects of neuroprotection and neurotoxicity. We investigated gene expression in brain tissue of adult mice treated with ketamine to characterize the expression profiles and to identify the affected metabolic pathways. Adult male mice were treated by a single intraperitoneal (i.p.) injection of either s(+)ketamine (80 mg/kg) or distilled water (as the control). Fifty genes were differentially expressed in ketamine-treated mouse brains compared with control mice using oligonucleotide microarray analysis, and the expression of Troponin T1 (Tnnt1) gene was consistently elevated (2- to 4-fold) (p<0.001). Ketamine-induced Tnnt1 expression was confirmed and characterized using RNA in situ hybridization techniques in paraffin embedded brain tissue sections. Tnnt1 expression was induced in the granule layer of the hippocampus, amygdala, hypothalamus, Purkinje cells of cerebellum (p<0.0001), and cerebral cortex. Tnnt1 gene is known to interact directly with FoxO1, which is involved in multiple peripheral metabolic pathways and central energy homeostasis. Our findings suggest that the induction of Tnnt1 gene expression in adult mouse brains by ketamine may illustrate the genes involved in the metabolic syndromes observed in neuropsychiatric disorders.
谷氨酸能系统与神经精神疾病有关，如精神分裂症、双相情感障碍和阿尔茨海默病，这些疾病中代谢综合征的患病率也很高。已知使用氯胺酮（一种非竞争性谷氨酸N-甲基-D-天冬氨酸（NMDA）受体拮抗剂）进行治疗具有神经保护和神经毒性的矛盾作用。我们研究了用氯胺酮治疗的成年小鼠脑组织中的基因表达，以表征表达谱并确定受影响的代谢途径。成年雄性小鼠通过单次腹腔注射s(+)氯胺酮（80mg/kg）或蒸馏水（作为对照）进行治疗。使用寡核苷酸微阵列分析，与对照小鼠相比，氯胺酮处理的小鼠脑中50个基因表达存在差异，肌钙蛋白T1（Tnnt1）基因的表达持续升高（2至4倍）（p<0.001）。使用石蜡包埋脑组织切片中的RNA原位杂交技术证实并表征了氯胺酮诱导的Tnnt1表达。在海马体、杏仁核、下丘脑、小脑浦肯野细胞（p<0.0001）和大脑皮层的颗粒层中诱导了Tnnt1表达。已知Tnnt1基因直接与FoxO1相互作用，FoxO1参与多种外周代谢途径和中枢能量稳态。我们的研究结果表明，氯胺酮在成年小鼠脑中诱导Tnnt1基因表达可能说明了神经精神疾病中观察到的代谢综合征所涉及的基因。
