Department of Biological Psychiatry, Tohoku University Graduate School of Medicine, Sendai, Japan.
Bipolar Disord. 2011 Aug-Sep;13(5-6):486-99. doi: 10.1111/j.1399-5618.2011.00946.x.
Mood stabilizers influence the morphology, chemotaxis, and survival of neurons, which are considered to be related to the mood-stabilizing effects of these drugs. Although previous studies suggest glial abnormalities in patients with bipolar disorder and an effect of mood stabilizers on certain genes in astrocytes, less is known about the effects of mood stabilizers in astrocytes than in neurons. The present study identifies a common underlying response to mood stabilizers in astrocytes.
Human astrocyte-derived cells (U-87 MG) were treated with the four most commonly used mood stabilizers (lithium, valproic acid, carbamazepine, and lamotrigine) and subjected to microarray gene expression analyses. The most prominently regulated genes were validated by qRT-PCR and western blot analysis. The intercellular localization of one of these regulated genes, fasciculation and elongation protein zeta 1 (FEZ1), was evaluated by immunofluorescence staining.
The microarray data indicated that FEZ1 was the only gene commonly induced by the four mood stabilizers in human astrocyte-derived cells. An independent experiment confirmed astrocytic FEZ1 induction at both the transcript and protein levels following mood stabilizer treatments. FEZ1 localized to the cytoplasm of transformed and primary astrocytes from the human adult brain.
Our data suggest that FEZ1 may play important roles in human astrocytes, and that mood stabilizers might exert their cytoprotective and mood-stabilizing effects by inducing FEZ1 expression in astrocytes.
心境稳定剂影响神经元的形态、趋化性和存活，这些被认为与这些药物的心境稳定作用有关。虽然先前的研究表明双相情感障碍患者存在神经胶质异常，以及心境稳定剂对星形胶质细胞中某些基因的影响，但对于心境稳定剂对星形胶质细胞的影响知之甚少，而不是神经元。本研究确定了星形胶质细胞对心境稳定剂的共同潜在反应。
用人星形胶质细胞衍生细胞（U-87 MG）用四种最常用的心境稳定剂（锂、丙戊酸、卡马西平和拉莫三嗪）处理，并进行微阵列基因表达分析。通过 qRT-PCR 和 Western blot 分析验证最显著调节的基因。通过免疫荧光染色评估其中一个调节基因（成束和伸长蛋白 ζ1（FEZ1）的细胞内定位。
微阵列数据表明，FEZ1 是四种心境稳定剂在人星形胶质细胞衍生细胞中唯一共同诱导的基因。一项独立的实验证实，在心境稳定剂处理后，FEZ1 在转录和蛋白质水平上均诱导星形胶质细胞。FEZ1 定位于来自人类成年大脑的转化和原代星形胶质细胞的细胞质中。
我们的数据表明 FEZ1 可能在人星形胶质细胞中发挥重要作用，并且心境稳定剂可能通过诱导 FEZ1 在星形胶质细胞中的表达来发挥其细胞保护和稳定情绪的作用。
