Model Mice for Mild-Form Glycine Encephalopathy: Behavioral and Biochemical Characterizations and Efficacy of Antagonists for the Glycine Binding Site of N-Methyl D-Aspartate Receptor
Model Mice for Mild-Form Glycine Encephalopathy: Behavioral and Biochemical Characterizations and Efficacy of Antagonists for the Glycine Binding Site of N-Methyl D-Aspartate Receptor
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DOI：
10.1203/pdr.0b013e3181799562
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发表时间：
2008-09
影响因子：
3.6
通讯作者：
Kanako Kojima‐Ishii;S. Kure;A. Ichinohe;T. Shinka;A. Narisawa;Shoko Komatsuzaki;J. Kanno;Fumiaki Kamada;Y. Aoki;H. Yokoyama;M. Oda;T. Sugawara;K. Mizoi;D. Nakahara;Y. Matsubara
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文献类型：
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作者：
Kanako Kojima‐Ishii;S. Kure;A. Ichinohe;T. Shinka;A. Narisawa;Shoko Komatsuzaki;J. Kanno;Fumiaki Kamada;Y. Aoki;H. Yokoyama;M. Oda;T. Sugawara;K. Mizoi;D. Nakahara;Y. Matsubara
甘氨酸脑病（Glycine encephalopathy，GE）是由遗传性甘氨酸裂解系统（Glycine cleavage system，GCS）缺陷引起的，其特征是甘氨酸在体液中蓄积和各种神经系统症状。典型GE的新生儿出现昏迷和惊厥，而轻度GE的婴儿期和儿童期出现精神发育迟滞和行为异常。最近，我们建立了具有降低的GCS活性（野生型（WT）C57 BL/6的29%）和脑中甘氨酸积累的转基因小鼠系（低GCS）（Stroke，2007; 38：2157）。本研究的目的是描述低GCS小鼠作为轻度GE模型的行为特征。还分析了另外两种转基因小鼠系：GCS活性升高的高GCS小鼠和GCS活性降低的低GCS-2小鼠。与对照组相比，低GCS小鼠表现出癫痫发作易感性增加，攻击性和焦虑样活动，这类似于轻度GE中报告的异常行为，而高GCS小鼠对癫痫发作不敏感，活动减退和焦虑较少。N-甲基-D-天冬氨酸受体甘氨酸结合位点的拮抗剂显著改善了低GCS小鼠的自发活动和癫痫发作易感性。我们的研究结果表明，低GCS小鼠作为轻度GE的小鼠模型和一种新的治疗策略是有用的。
Glycine encephalopathy (GE) is caused by an inherited deficiency of the glycine cleavage system (GCS) and characterized by accumulation of glycine in body fluids and various neurologic symptoms. Coma and convulsions develop in neonates in typical GE while psychomotor retardation and behavioral abnormalities in infancy and childhood are observed in mild GE. Recently, we have established a transgenic mouse line (low-GCS) with reduced GCS activity (29% of wild-type (WT) C57BL/6) and accumulation of glycine in the brain (Stroke, 2007; 38:2157). The purpose of the present study is to characterize behavioral features of the low-GCS mouse as a model of mild GE. Two other transgenic mouse lines were also analyzed: high-GCS mice with elevated GCS activity and low-GCS-2 mice with reduced GCS activity. As compared with controls, low-GCS mice manifested increased seizure susceptibility, aggressiveness and anxiety-like activity, which resembled abnormal behaviors reported in mild GE, whereas high-GCS mice were less sensitive to seizures, hypoactive and less anxious. Antagonists for the glycine-binding site of the N-methyl-D-aspartate receptor significantly ameliorated elevated locomotor activity and seizure susceptibility in the low-GCS mice. Our results suggest the usefulness of low-GCS mice as a mouse model for mild GE and a novel therapeutic strategy.