Deane Katrina E, Binder Devin K, Razak Khaleel A
Psychology Department, University of California, Riverside, 900 University Ave, Riverside, CA 92521, USA.
Graduate Neuroscience Program, University of California, Riverside, 900 University Ave, Riverside, CA 92521, USA; Biomedical Sciences, School of Medicine, University of California, Riverside, 900 University Ave, Riverside, CA 92521, USA.
Neurobiol Dis. 2025 Aug;212:106963. doi: 10.1016/j.nbd.2025.106963. Epub 2025 May 18.
Fragile X Syndrome (FXS) is a leading genetic cause of autism spectrum disorders (ASD)- associated behaviors, including sensory processing deficits. Sensory sensitivity and temporal processing deficits in the auditory domain will affect development of language and cognitive functions. The mouse model for FXS, Fmr1 KO, has shown remarkably similar auditory processing phenotypes to patients with FXS. In vitro cortical slice recordings show layer-specific differences in Fmr1 KO mouse local circuits, but it is unclear how these differences translate to changes in sensory processing. In this study, we used a depth multielectrode to record in vivo spikes and local field potentials across layers of the auditory cortex in Fmr1 KO and wildtype mice (WT), converting the latter to current source density (CSD) profiles for improved spatial resolution analysis. We observed reduced CSD sink amplitudes and inter-trial phase coherence, and an increase in trial-to-trial variability for temporally modulated stimuli in the KO mice. Results indicated a differential cortical layer pattern of activity in KO mice, with higher baseline gamma power in superficial and deep layers and higher resting delta and theta power in granular layers. Significantly elevated inter-trial variability was observed for CSD and spikes in KO mice. Auditory steady state responses to clicks or gaps at 40 Hz showed considerable trial-to-trial variability in a layer-specific manner in KO mice. Neural generators in the Fmr1 KO mouse auditory cortex failed to detect short gaps in noise, indicating severe temporal processing deficits. Altogether, this study indicates layer-specific cortical mechanisms of sensory hypersensitivity and temporal processing deficits in FXS.
脆性X综合征（FXS）是自闭症谱系障碍（ASD）相关行为的主要遗传原因，包括感觉处理缺陷。听觉领域的感觉敏感性和时间处理缺陷会影响语言和认知功能的发展。FXS的小鼠模型Fmr1基因敲除小鼠（Fmr1 KO）已显示出与FXS患者非常相似的听觉处理表型。体外皮质切片记录显示Fmr1 KO小鼠局部回路存在层特异性差异，但尚不清楚这些差异如何转化为感觉处理的变化。在本研究中，我们使用深度多电极记录Fmr1 KO小鼠和野生型小鼠（WT）听觉皮质各层的体内动作电位和局部场电位，并将野生型小鼠的记录转换为电流源密度（CSD）分布图，以改进空间分辨率分析。我们观察到KO小鼠中CSD下沉幅度和试验间相位相干性降低，以及对时间调制刺激的试验间变异性增加。结果表明KO小鼠的皮质层活动模式存在差异，浅层和深层的基线γ功率较高，颗粒层的静息δ和θ功率较高。KO小鼠的CSD和动作电位的试验间变异性显著升高。KO小鼠对40Hz的点击或间隙的听觉稳态反应在各层中均表现出明显的试验间变异性。Fmr1 KO小鼠听觉皮质中的神经发生器无法检测到噪声中的短间隙，表明存在严重的时间处理缺陷。总之，本研究表明FXS中感觉超敏和时间处理缺陷的层特异性皮质机制。
