Takebayashi Hironao, Yamamoto Naoki, Umino Asami, Nishikawa Toru
Section of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
Int J Neuropsychopharmacol. 2009 Sep;12(8):1111-26. doi: 10.1017/S1461145709009997. Epub 2009 Mar 2.
The onset of schizophrenia and the schizophrenomimetic effects of an N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, rarely occur during infancy and childhood, suggesting that schizophrenia-related neuron circuits and molecules in the brain might show an age-related response to an NMDA receptor antagonist. By using a DNA microarray technique, we have identified the developmentally regulated PCP-inducible gene leiomodin2 (Lmod2) that encodes a tropomyosin-binding actin-capping protein enriched in the cardiac and skeletal muscles. PCP caused an increase in the thalamic amounts of Lmod2 transcripts at postnatal days (PD) 32 and 50 without affecting them at PD 8, 13, 20 and 24, while the NMDA antagonist failed to produce a significant change in the gene expression in the adult heart. In-situ hybridization analysis revealed that the basal and PCP-induced expression of the Lmod2 gene is almost confined to the lateral and anterior nuclei of the thalamus among the brain regions at PD 50. The PCP-induced up-regulation of Lmod2 mRNAs in the adult thalamus was mimicked totally (also up-regulated) by another NMDA antagonist, dizocilpine, and partly by the indirect dopamine agonist, methamphetamine. Moreover, pretreatment with a D(2)-preferring dopamine receptor antagonist, haloperidol, partially antagonizes the increasing effects of PCP on thalamic Lmod2 gene expression. These findings suggest that Lmod2 might be involved in the pathophysiology of the age-dependent onset of drug-induced schizophrenia-like psychosis and schizophrenia and that the limited thalamic nuclei expressing the Lmod2 gene could compose the neuron circuits that are specifically disturbed in these mental disorders.
精神分裂症的发病以及 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂氯胺酮的拟精神分裂症效应在婴儿期和儿童期很少出现，这表明大脑中与精神分裂症相关的神经回路和分子可能对 NMDA 受体拮抗剂表现出年龄相关的反应。通过使用 DNA 微阵列技术，我们鉴定出了发育调控的苯环己哌啶（PCP）诱导基因 leiomodin2（Lmod2），该基因编码一种富含于心肌和骨骼肌中的原肌球蛋白结合肌动蛋白封端蛋白。PCP 在出生后第 32 天和第 50 天导致丘脑 Lmod2 转录本数量增加，而在出生后第 8 天、第 13 天、第 20 天和第 24 天未对其产生影响，而 NMDA 拮抗剂未能使成年心脏中的基因表达发生显著变化。原位杂交分析显示，在出生后第 50 天，Lmod2 基因的基础表达和 PCP 诱导的表达几乎局限于大脑区域中的丘脑外侧核和前核。另一种 NMDA 拮抗剂地佐环平完全模拟了（同样上调）成年丘脑中 PCP 诱导的 Lmod2 mRNA 上调，间接多巴胺激动剂甲基苯丙胺则部分模拟了这种上调。此外，用 D2 偏好性多巴胺受体拮抗剂氟哌啶醇预处理可部分拮抗 PCP 对丘脑 Lmod2 基因表达的增加作用。这些发现表明，Lmod2 可能参与药物诱导性精神分裂症样精神病和精神分裂症年龄依赖性发病的病理生理学过程，并且表达 Lmod2 基因的有限丘脑核可能构成了在这些精神障碍中受到特异性干扰的神经回路。
