Aggressive-like behavior and increased glycine transporters in a zebrafish model of CHARGE syndrome
Aggressive-like behavior and increased glycine transporters in a zebrafish model of CHARGE syndrome
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DOI：
10.1016/j.bbr.2019.112293
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发表时间：
2020-01-27
影响因子：
2.7
通讯作者：
Liu, Zhi-Zhi
中科院分区：
文献类型：
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作者：
Liu, Hui;Liu, Zhi-Zhi
先天性缺损、心脏缺陷、后鼻孔闭锁、生长发育受限、生殖器发育不全、耳畸形和/或听力丧失（CHARGE）综合征是一种先天性疾病，主要由染色体结构域解旋酶DNA结合蛋白7（chd 7）内的突变引起。CHARGE综合征中的行为异常已得到解决，但其潜在机制仍知之甚少。在这里，我们进行了四个行为测试，包括开放领域的测试，新的坦克测试，浅水测试和镜像诱导攻击测试，在chd 7杂合子斑马鱼突变体，以表征行为异常的斑马鱼模型的CHARGE综合征。我们发现chd 7杂合子突变体在旷场试验和镜像诱导攻击试验中分别表现出焦虑样行为和攻击样行为，这与人类CHARGE综合征中报告的行为异常相似。此外，我们发现甘氨酸和D-环丝氨酸处理拯救了chd 7杂合斑马鱼突变体的攻击行为，表明chd 7杂合斑马鱼突变体脑中的兴奋和抑制平衡可能被破坏。进一步的分析表明，在chd 7杂合突变的斑马鱼脑中，甘氨酸转运蛋白的表达显著增加。用甘氨酸转运蛋白1的抑制剂肌氨酸治疗，部分挽救了chd 7杂合子斑马鱼突变体的攻击性行为。综上所述，我们的数据表明，CHARGE综合征的攻击行为可能是由于甘氨酸转运蛋白表达增加，抑制甘氨酸转运蛋白的活性可能是治疗CHARGE综合征行为异常的一种方法。
Coloboma, heart defects, choanal atresia, restricted growth and development, genital hypoplasia, ear abnormalities and/or hearing loss (CHARGE) syndrome is a congenital disorder that is mainly caused by mutations within chromodomain helicase DNA-binding protein 7 (chd7). Behavioral abnormalities have been addressed in CHARGE syndrome, but the underlying mechanisms are still poorly understood. Here, we performed four behavioral tests-including the open-field test, novel-tank test, shoaling test and mirror-induced attack test-in chd7 heterozygous zebrafish mutants in order to characterize the behavioral abnormalities in a zebrafish model of CHARGE syndrome. We found that chd7 heterozygous mutants exhibited anxious-like behavior and aggressive-like behavior in the open-field test and in the mirror-induced attack test, respectively, which resembled the reported behavioral abnormalities in CHARGE syndrome in humans. Moreover, we found that glycine and D-cycloserine treatment rescued the aggressive behavior of chd7 heterozygous zebrafish mutants, indicating that the excitation and inhibition balance might be disrupted in the brains of chd7 heterozygous zebrafish mutants. Further analysis showed that the expression of glycine transporters was dramatically increased in the brains of chd7 heterozygous zebrafish mutants. Treatment with an inhibitor of glycine transporter 1, sarcosine, partially rescued the aggressive-like behavior of chd7 heterozygous zebrafish mutants. Taken together, our data suggest that the aggressive behavior in CHARGE syndrome may be due to the increased expression of glycine transporters, and inhibition of the activity of glycine transporters may be an approach to treat the behavioral abnormalities in CHARGE syndrome.