Graduate Neuroscience Program, University of California, Riverside, United States of America.
Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, United States of America.
Neurobiol Dis. 2024 Oct 1;200:106628. doi: 10.1016/j.nbd.2024.106628. Epub 2024 Aug 5.
Autism Spectrum Disorders (ASD) encompass a wide array of debilitating symptoms, including severe sensory deficits and abnormal language development. Sensory deficits early in development may lead to broader symptomatology in adolescents and adults. The mechanistic links between ASD risk genes, sensory processing and language impairment are unclear. There is also a sex bias in ASD diagnosis and symptomatology. The current study aims to identify the developmental trajectory and genotype- and sex-dependent differences in auditory sensitivity and temporal processing in a Pten-deletion (phosphatase and tensin homolog missing on chromosome 10) mouse model of ASD. Auditory temporal processing is crucial for speech recognition and language development and deficits will cause language impairments. However, very little is known about the development of temporal processing in ASD animal models, and if there are sex differences. To address this major gap, we recorded epidural electroencephalography (EEG) signals from the frontal (FC) and auditory (AC) cortex in developing and adult Nse-cre PTEN mice, in which Pten is deleted in specific cortical layers (layers III-V) (PTEN conditional knock-out (cKO). We quantified resting EEG spectral power distribution, auditory event related potentials (ERP) and temporal processing from awake and freely moving male and female mice. Temporal processing is measured using a gap-in-noise-ASSR (auditory steady state response) stimulus paradigm. The experimental manipulation of gap duration and modulation depth allows us to measure cortical entrainment to rapid gaps in sounds. Temporal processing was quantified using inter-trial phase clustering (ITPC) values that account for phase consistency across trials. The results show genotype differences in resting power distribution in PTEN cKO mice throughout development. Male and female cKO mice have significantly increased beta power but decreased high frequency oscillations in the AC and FC. Both male and female PTEN cKO mice show diminished ITPC in their gap-ASSR responses in the AC and FC compared to control mice. Overall, deficits become more prominent in adult (p60) mice, with cKO mice having significantly increased sound evoked power and decreased ITPC compared to controls. While both male and female cKO mice demonstrated severe temporal processing deficits across development, female cKO mice showed increased hypersensitivity compared to males, reflected as increased N1 and P2 amplitudes. These data identify a number of novel sensory processing deficits in a PTEN-ASD mouse model that are present from an early age. Abnormal temporal processing and hypersensitive responses may contribute to abnormal development of language function in ASD.
自闭症谱系障碍（ASD）包括一系列严重的症状，包括严重的感觉缺陷和语言发育异常。早期发育中的感觉缺陷可能导致青少年和成年人出现更广泛的症状。ASD 风险基因、感觉处理和语言障碍之间的机制联系尚不清楚。ASD 的诊断和症状也存在性别偏见。本研究旨在确定一种 ASD 鼠模型中听觉敏感性和时间处理的发育轨迹以及基因型和性别依赖性差异，该模型为 Pten 缺失（染色体 10 上缺失磷酸酶和张力蛋白同源物）。听觉时间处理对语音识别和语言发展至关重要，而缺陷会导致语言障碍。然而，对于 ASD 动物模型中时间处理的发展，以及是否存在性别差异，我们知之甚少。为了解决这个主要差距，我们记录了发育中和成年 Nse-cre PTEN 小鼠的额（FC）和听觉（AC）皮层的硬膜外脑电图（EEG）信号，其中 Pten 在特定皮层层（III-V 层）中缺失（PTEN 条件敲除（cKO）。我们量化了来自清醒和自由移动的雄性和雌性小鼠的静息 EEG 频谱功率分布、听觉事件相关电位（ERP）和时间处理。时间处理是使用噪声中的间隙-ASSR（听觉稳态反应）刺激范式来测量的。间隙持续时间和调制深度的实验操作允许我们测量皮质对声音中快速间隙的跟随。使用跨试验相位聚类（ITPC）值来量化时间处理，该值考虑了试验之间的相位一致性。结果显示，PTEN cKO 小鼠在整个发育过程中的静息功率分布存在基因型差异。雄性和雌性 cKO 小鼠的 AC 和 FC 中的β功率显著增加，但高频振荡减少。与对照小鼠相比，雄性和雌性 PTEN cKO 小鼠的 AC 和 FC 中的间隙-ASSR 反应的 ITPC 明显降低。总体而言，与对照相比，在成年（p60）小鼠中缺陷更为明显，cKO 小鼠的声音诱发功率显著增加，ITPC 降低。虽然雄性和雌性 cKO 小鼠在整个发育过程中都表现出严重的时间处理缺陷，但与雄性相比，雌性 cKO 小鼠表现出更高的超敏反应，表现为 N1 和 P2 幅度增加。这些数据在 PTEN-ASD 小鼠模型中确定了一些新的感觉处理缺陷，这些缺陷从早期就存在。异常的时间处理和超敏反应可能导致 ASD 中语言功能的异常发展。
