Molecular causes of sex-specific deficits in rodent models of neurodevelopmental disorders.
Molecular causes of sex-specific deficits in rodent models of neurodevelopmental disorders.
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DOI：
10.1002/jnr.24577
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发表时间：
2021-01
影响因子：
4.2
通讯作者：
Manzini MC
中科院分区：
文献类型：
--
作者：
Mossa A;Manzini MC
神经发育障碍(NDDS)，如智力残疾和自闭症谱系障碍，在患病率上一直显示出男性偏见，但尚不清楚为什么男性和女性受到影响的频率不同。虽然许多转基因NDD模型的行为研究只关注雄性，但美国国立卫生研究院要求将性别作为一个生物变量，这促进了野生型和突变动物中雄性和雌性表现的比较。在这里，我们回顾了NDDS啮齿动物模型的例子，在这些模型中，在分子、生理和/或行为反应中发现了性别特异性缺陷，表明在NDDS基因突变的易感性上存在性别差异。涉及突触功能(GABRB3和NRXN1)、染色质重塑(CHD8、EMHT1和ADNP)以及细胞内信号(CC2D1A和ERK1)等机制的基因单倍体不足会导致男性更严重的行为后果。然而，在没有行为缺陷的情况下，女性仍然可以出现细胞和电生理变化，这可能是由于代偿机制或分子和细胞功能在两性中的差异分配造成的。通过将这些发现与雌性受到更严重影响的小鼠模型(MTHFR和AMBRA1)进行对比，我们提出了一个框架来研究可能导致NDDS性别偏见的性别特异性缺陷。
Neurodevelopmental disorders (NDDs) such as intellectual disability and autism spectrum disorder consistently show a male bias in prevalence, but it remains unclear why males and females are affected with different frequency. While many behavioral studies of transgenic NDD models have focused only on males, the requirement by the National Institutes of Health to consider sex as a biological variable has promoted the comparison of male and female performance in wild‐type and mutant animals. Here, we review examples of rodent models of NDDs in which sex‐specific deficits were identified in molecular, physiological, and/or behavioral responses, showing sex differences in susceptibility to disruption of genes mutated in NDDs. Haploinsufficiency in genes involved in mechanisms such as synaptic function (GABRB3 and NRXN1), chromatin remodeling (CHD8, EMHT1, and ADNP), and intracellular signaling (CC2D1A and ERK1) lead to more severe behavioral outcomes in males. However, in the absence of behavioral deficits, females can still present with cellular and electrophysiological changes that could be due to compensatory mechanisms or differential allocation of molecular and cellular functions in the two sexes. By contrasting these findings with mouse models where females are more severely affected (MTHFR and AMBRA1), we propose a framework to approach the study of sex‐specific deficits possibly leading to sex bias in NDDs.
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影响因子：
3.2
作者：
Auger AP;Olesen KM
通讯作者：
Olesen KM
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作者：
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通讯作者：
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