Duncan Carlotta E, Chetcuti Albert F, Schofield Peter R
Neuroscience Research Program, Garvan Institute, Sydney, Australia.
Psychiatr Genet. 2008 Oct;18(5):226-39. doi: 10.1097/YPG.0b013e3283053019.
Antipsychotic drugs are the most effective treatment for the psychotic symptoms of schizophrenia, yet their mechanism of action remains largely unknown.
Earlier studies have shown gene expression changes in rodent brains after treatment with antipsychotic drugs. We aimed to further characterize these changes using whole-genome transcript profiling to explore coregulation of genes after multiple antipsychotic drug treatment studies.
This study involved transcript profile analysis after 7-day treatment of inbred C57BL/6 mice with conventional (haloperidol) or atypical (clozapine or olanzapine) antipsychotic drugs. Microarray analysis was undertaken using whole-brain mRNA on Affymetrix 430v2 arrays, with quantitative reverse transcriptase-PCR used to confirm gene expression changes. Western blotting was also used to explore translation of gene dysregulation to protein changes and to explore anatomical specificity of such changes.
Thirteen genes showed verified regulation by multiple antipsychotic drugs - three genes significantly upregulated and 10 genes significantly downregulated by treatment. These genes encode proteins that function in various biological processes including neurogenesis, cell adhesion, and four genes are involved in voltage-gated ion channels: neural precursor cell developmentally downregulated gene 4 (Nedd4), Kv channel interacting protein 3 (KChip3), potassium voltage-gated channel, shaker-related subfamily, alpha1 (Kcna1) encoding Kv1.1 protein and beta1 (Kcnab1) encoding Kvbeta1 protein. The translation of these gene expression changes to protein dysregulation for Kv1.1, KCHIP3, and NEDD4 was confirmed by western blot, with regional protein analyses undertaken for Kv1.1 and KCHIP3.
These results suggest that transcriptional regulation of ion channels, crucial for neurotransmission, may play a role in mediating antipsychotic drug effects.
抗精神病药物是治疗精神分裂症精神病性症状最有效的药物，但其作用机制仍 largely 未知。
早期研究显示抗精神病药物治疗后啮齿动物大脑中的基因表达发生变化。我们旨在通过全基因组转录谱分析进一步表征这些变化，以探索多次抗精神病药物治疗研究后基因的共调节情况。
本研究涉及用传统（氟哌啶醇）或非典型（氯氮平或奥氮平）抗精神病药物对近交系 C57BL/6 小鼠进行 7 天治疗后的转录谱分析。使用 Affymetrix 430v2 芯片对全脑 mRNA 进行微阵列分析，并用定量逆转录聚合酶链反应来确认基因表达变化。蛋白质印迹法也用于探索基因失调向蛋白质变化的转化，并探索此类变化的解剖学特异性。
13 个基因显示受到多种抗精神病药物的调控——3 个基因显著上调，10 个基因显著下调。这些基因编码的蛋白质在包括神经发生、细胞黏附等各种生物学过程中发挥作用，并且有 4 个基因参与电压门控离子通道：神经前体细胞发育下调基因 4（Nedd4）、Kv 通道相互作用蛋白 3（KChip3）、钾电压门控通道、与震颤相关亚家族、编码 Kv1.1 蛋白的α1（Kcna1）和编码 Kvbeta1 蛋白的β1（Kcnab1）。通过蛋白质印迹法证实了这些基因表达变化向 Kv1.1、KCHIP3 和 NEDD4 蛋白质失调的转化，并对 Kv1.1 和 KCHIP3 进行了区域蛋白质分析。
这些结果表明，对神经传递至关重要的离子通道的转录调控可能在介导抗精神病药物作用中发挥作用。
