Diminished activity-dependent BDNF signaling differentially causes autism-like behavioral deficits in male and female mice.
Diminished activity-dependent BDNF signaling differentially causes autism-like behavioral deficits in male and female mice.
复制标题
依赖活性的BDNF信号差异差异会导致雄性和雌性小鼠的自闭症样行为缺陷。
DOI：
10.3389/fpsyt.2023.1182472
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发表时间：
2023
影响因子：
4.7
通讯作者：
Qin, Luye
中科院分区：
文献类型：
--
作者：
Ma, Kaijie;Taylor, Connie;Williamson, Mark;Newton, Samuel S. S.;Qin, Luye
关键词：
自闭症谱系障碍(ASD)是一组遗传异质性很强的神经发育障碍，男性多于女性。最近的人类遗传学研究发现了多个ASD的高危基因，这些基因产生了相似的表型，表明不同的遗传因素汇聚到共同的分子途径。我们和其他人假设，在ASD中，活动依赖的神经信号是一个聚集性的分子通路，调节失调。然而，活动依赖神经信号减弱与ASD之间的因果联系仍不清楚。脑源性神经营养因子(BDNF)是介导活性依赖性神经信号转导的关键分子。因此，我们假设依赖活动的BDNF信号减弱可能会导致自闭症样的行为缺陷。在这里，我们利用人类BDNF蛋氨酸(Met)等位基因的基因敲入的小鼠，在不改变基础BDNF水平的情况下，减少了活动依赖的BDNF的释放，从而研究了活动依赖的BDNF信号减弱对孤独症样行为缺陷的影响。与野生型(WT)对照组相比，活动依赖的BDNF信号减弱同样会在雄性和雌性小鼠中引发类似焦虑的行为。值得注意的是，依赖活动的BDNF信号减弱在雄性和雌性小鼠中不同地导致了自闭症样的社会缺陷和自我修饰的增加，并且雄性小鼠比雌性小鼠更严重。同样，在雌性BDNF+/Met小鼠中观察到了性别二态空间记忆缺陷，但在雄性BDNF+/Met小鼠中没有观察到。我们的研究不仅揭示了依赖活动的BDNF信号减弱与ASD样行为缺陷之间的因果联系，而且还发现了ASD中先前被低估的活动依赖BDNF信号减弱的性别特异性影响。这些带有人类BDNF Met变体基因敲入的小鼠为研究活动依赖神经信号减弱的细胞和分子机制提供了一个独特的小鼠模型，活动依赖神经信号是ASD中调节失调的常见分子途径。
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with strong genetic heterogeneity and more prevalent in males than females. Recent human genetic studies have identified multiple high-risk genes for ASD, which produce similar phenotypes, indicating that diverse genetic factors converge to common molecular pathways. We and others have hypothesized that activity-dependent neural signaling is a convergent molecular pathway dysregulated in ASD. However, the causal link between diminished activity-dependent neural signaling and ASD remains unclear. Brain-derived neurotrophic factor (BDNF) is a key molecule mediating activity-dependent neural signaling. We therefore hypothesize that diminished activity-dependent BDNF signaling could confer autism-like behavioral deficits. Here, we investigated the effect of diminished activity-dependent BDNF signaling on autism-like behavioral deficits by using mice with genetic knock-in of a human BDNF methionine (Met) allele, which has decreased activity-dependent BDNF release without altering basal BDNF level. Compared with wild-type (WT) controls, diminished activity-dependent BDNF signaling similarly induced anxiety-like behaviors in male and female mice. Notably, diminished activity-dependent BDNF signaling differentially resulted in autism-like social deficits and increased self-grooming in male and female mice, and male mice were more severe than female mice. Again, sexually dimorphic spatial memory deficits were observed in female BDNF+/Met mice, but not in male BDNF+/Met mice. Our study not only reveals a causal link between diminished activity-dependent BDNF signaling and ASD-like behavioral deficits, but also identifies previously underappreciated sex-specific effect of diminished activity-dependent BDNF signaling in ASD. These mice with genetic knock-in of the human BDNF Met variant provide a distinct mouse model for studying the cellular and molecular mechanisms underlying diminished activity-dependent neural signaling, the common molecular pathway dysregulated in ASD.
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影响因子：
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通讯作者：
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影响因子：
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