Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model
Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model
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DOI：
10.1136/jmg.2008.061796
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发表时间：
2009-02-01
影响因子：
4
通讯作者：
Ethell, I. M.
中科院分区：
文献类型：
--
作者：
Bilousova, T. V.;Dansie, L.;Ethell, I. M.
背景：脆性X染色体综合征（脆性X染色体综合征，FXS）是最常见的单基因遗传形式的智力低下，其行为在自闭症谱系中是极端的。FXS和脆性X智力迟钝基因敲除（Fmr1 KO）小鼠（FXS的动物模型）的受试者显示树突脊柱成熟缺陷，这可能是FXS认知和行为异常的基础。二甲胺四环素是一种四环素类似物，已用于中风、多发性硬化症和几种神经退行性疾病的临床试验。方法：我们评估了二甲胺四环素对幼年Fmr1 KO小鼠海马树突棘发育的影响，以及从这些小鼠分离的海马神经元的原代培养。米诺环素对幼年WT和Fmr1 KO小鼠的认知影响也通过常规认知、活动和焦虑的既定行为测试进行评估。结果：我们的研究表明二甲胺四环素促进树突脊柱在培养和体内成熟。米诺环素对树突脊柱形态的有益影响也伴随着3周龄Fmr1 KO小鼠行为表现的改变。与未治疗的Fmr1 KO小鼠相比，二甲胺四环素治疗的Fmr1 KO小鼠在升高+迷宫中表现出较少的焦虑，在Y迷宫中表现出更多的战略性探索行为。我们的数据表明，米诺环素的这些作用可能与它对MMP-9的表达和活性的抑制作用有关，MMP-9在Fmr1 KO小鼠海马中的表达和活性更高。结论：米诺环素是治疗脆性X型智力迟钝的有效药物。
Background: Fragile X syndrome (FXS) is the most common single gene inherited form of mental retardation, with behaviours at the extreme of the autistic spectrum. Subjects with FXS and fragile X mental retardation gene knock out (Fmr1 KO) mice, an animal model for FXS, have been shown to exhibit defects in dendritic spine maturation that may underlie cognitive and behavioural abnormalities in FXS. Minocycline is a tetracycline analogue that has been used in clinical trials for stroke, multiple sclerosis and several neurodegenerative conditions.Methods: We evaluated the effects of minocycline on dendritic spine development in the hippocampus of young Fmr1 KO mice, and in primary cultures of hippocampal neurons isolated from those mice. Cognitive effects of minocycline in young WT and Fmr1 KO mice were also evaluated using established behavioural tests for general cognition, activity and anxiety.Results: Our studies demonstrate that minocycline promotes dendritic spine maturation both in cultures and in vivo. The beneficial effects of minocycline on dendritic spine morphology are also accompanied by changes in the behavioural performance of 3-week-old Fmr1 KO mice. Minocycline treated Fmr1 KO mice show less anxiety in the elevated plus maze and more strategic exploratory behaviour in the Y maze as compared to untreated Fmr1 KO mice. Our data suggest that these effects of minocycline may relate to its inhibitory action on MMP-9 expression and activity, which are higher in the hippocampus of Fmr1 KO mice.Conclusion: These findings establish minocycline as a promising therapeutic for the treatment of fragile X mental retardation.