背景:自闭症谱系障碍(ASD)目前在美国44名儿童中约有1名被诊断出,基于各种各样的症状,包括感觉功能障碍和语言发育异常。男孩的诊断频率是女孩的3.8倍。听觉时间处理对于语音识别和语言发展至关重要。时间处理的异常发展可能是ASD语言障碍的原因。时间处理发展的性别差异可能是ASD男女儿童语言结果差异的基础。要了解时间处理中潜在性别差异的机制,需要临床前模型。然而,在ASD的任何动物模型中,没有研究解决了整个发育过程中时间处理的性别差异。
方法:为了填补这一主要空白,我们比较了雄性和雌性野生型(WT)和Fmr1敲除(KO)小鼠的听觉时间处理的发展,脆性X综合征(FXS)模型,ASD相关行为的主要遗传原因。使用硬膜外螺钉电极,我们记录了听觉事件相关电位(ERP)和听觉时间处理,在年轻(出生后(p)21和p30)和成人(p60)年龄的听觉和额叶皮层清醒,自由移动的老鼠
结果:结果表明,与WT对应物相比,Fmr1KO小鼠在整个发育过程中的两种性别的ERP幅度均增强,成年雌性比成年雄性KO小鼠增强更大。缺口-ASSR赤字出现在额叶,但不是听觉,雌性KO小鼠早期发育中的皮质(p21)。与雄性KO小鼠不同,雌性KO小鼠在p30时显示WT样时间处理。两种性别的成年小鼠都没有时间处理缺陷。
结论:这些结果表明Fmr1KO小鼠的时间加工和超敏反应的发育轨迹存在性别差异。雄性KO小鼠表现出比雌性更慢的时间处理成熟。雌性KO小鼠在发育后期表现出比雄性更强的过敏反应。在各个发展的关键时期,时间加工和超敏反应的成熟率的差异可能导致语言功能的性别差异,FXS中的唤醒和焦虑。
BACKGROUND: Autism spectrum disorder (ASD) is currently diagnosed in approximately 1 in 44 children in the United States, based on a wide array of symptoms, including sensory dysfunction and abnormal language development. Boys are diagnosed ~ 3.8 times more frequently than girls. Auditory temporal processing is crucial for speech recognition and language development. Abnormal development of temporal processing may account for ASD language impairments. Sex differences in the development of temporal processing may underlie the differences in language outcomes in male and female children with ASD. To understand mechanisms of potential sex differences in temporal processing requires a preclinical model. However, there are no studies that have addressed sex differences in temporal processing across development in any animal model of ASD.
METHODS: To fill this major gap, we compared the development of auditory temporal processing in male and female wildtype (WT) and Fmr1 knock-out (KO) mice, a model of Fragile X Syndrome (FXS), a leading genetic cause of ASD-associated behaviors. Using epidural screw electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at young (postnatal (p)21 and p30) and adult (p60) ages from both auditory and frontal cortices of awake, freely moving mice.
RESULTS: The results show that ERP amplitudes were enhanced in both sexes of Fmr1 KO mice across development compared to WT counterparts, with greater enhancement in adult female than adult male KO mice. Gap-ASSR deficits were seen in the frontal, but not auditory, cortex in early development (p21) in female KO mice. Unlike male KO mice, female KO mice show WT-like temporal processing at p30. There were no temporal processing deficits in the adult mice of both sexes.
CONCLUSIONS: These results show a sex difference in the developmental trajectories of temporal processing and hypersensitive responses in Fmr1 KO mice. Male KO mice show slower maturation of temporal processing than females. Female KO mice show stronger hypersensitive responses than males later in development. The differences in maturation rates of temporal processing and hypersensitive responses during various critical periods of development may lead to sex differences in language function, arousal and anxiety in FXS.