Deletion of Fmr1 results in sex-specific changes in behavior.
Deletion of Fmr1 results in sex-specific changes in behavior.
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DOI：
10.1002/brb3.800
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发表时间：
2017-10
影响因子：
3.1
通讯作者：
Lugo JN
中科院分区：
文献类型：
--
作者：
Nolan SO;Reynolds CD;Smith GD;Holley AJ;Escobar B;Chandler MA;Volquardsen M;Jefferson T;Pandian A;Smith T;Huebschman J;Lugo JN
在这项研究中，我们使用了系统性的Fmr1基因敲除，以调查基因型和性别特异性差异，包括社交能力、重复行为、活动水平、焦虑和恐惧相关的学习和记忆的多项指标。脆性X综合征是智力残疾和自闭症最常见的单基因原因。到目前为止，很少有研究在脆性X综合征小鼠模型中研究性别差异，尽管临床数据支持两性之间总体患病率和表型存在差异的观点。使用野生型和系统性纯合子Fmr1敲除小鼠，我们评估了成年动物的各种行为范式，包括旷场试验、高架十字迷宫、鼻戳试验、加速旋转棒、社会分区任务、三室社会任务和两种不同的恐惧条件反射范式。测试的顺序是，最具侵入性的测试在序列中最后进行，类似行为的测试范例在单独的队列中进行，以尽量减少测试影响。我们的研究结果表明，在Fmr1基因敲除小鼠中有几种性别特异性变化，包括男性特异性活动水平增加，以及女性特异性重复行为增加，包括鼻子戳试验和加速旋转杆任务的运动协调。结果还表明，Fmr1缺失导致男女恐惧学习和记忆的缺陷，并且在两项任务中的社会行为没有变化。这些发现强调了在临床前研究中纳入女性受试者的重要性，因为简单地研究男性基因突变的影响并不能得出表型的全貌。进一步的研究应该探索这些性别之间的显着表型差异。此外，考虑到治疗策略在性别之间通常是等效的，结果强调了对性别特异性治疗的潜在需求。
In this study, we used a systemic Fmr1 knockout in order to investigate both genotype‐ and sex‐specific differences across multiple measures of sociability, repetitive behaviors, activity levels, anxiety, and fear‐related learning and memory. Fragile X syndrome is the most common monogenic cause of intellectual disability and autism. Few studies to date have examined sex differences in a mouse model of Fragile X syndrome, though clinical data support the idea of differences in both overall prevalence and phenotype between the sexes. Using wild‐type and systemic homozygous Fmr1 knockout mice, we assessed a variety of behavioral paradigms in adult animals, including the open field test, elevated plus maze, nose‐poke assay, accelerating rotarod, social partition task, three‐chambered social task, and two different fear conditioning paradigms. Tests were ordered such that the most invasive tests were performed last in the sequence, and testing paradigms for similar behaviors were performed in separate cohorts to minimize testing effects. Our results indicate several sex‐specific changes in Fmr1 knockout mice, including male‐specific increases in activity levels, and female‐specific increases in repetitive behaviors on both the nose‐poke assay and motor coordination on the accelerating rotarod task. The results also indicated that Fmr1 deletion results in deficits in fear learning and memory across both sexes, and no changes in social behavior across two tasks. These findings highlight the importance of including female subjects in preclinical studies, as simply studying the impact of genetic mutations in males does not yield a complete picture of the phenotype. Further research should explore these marked phenotypic differences among the sexes. Moreover, given that treatment strategies are typically equivalent between the sexes, the results highlight a potential need for sex‐specific therapeutics.
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DOI：
10.1002/ajmg.1320230128
发表时间：
1986-01-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
HAGERMAN, RJ;JACKSON, AW;BRADEN, M
通讯作者：
BRADEN, M
影响因子：
3.5
作者：
Peier, AM;McIlwain, KL;Nelson, DL
通讯作者：
Nelson, DL
影响因子：
2.5
作者：
McFadyen, MP;Kusek, G;Flaherty, L
通讯作者：
Flaherty, L
影响因子：
3
作者：
PELLOW, S;CHOPIN, P;BRILEY, M
通讯作者：
BRILEY, M
影响因子：
3.7
作者：
Pietropaolo S;Guilleminot A;Martin B;D'Amato FR;Crusio WE
通讯作者：
Crusio WE