Lovelace Jonathan W, Ethell Iryna M, Binder Devin K, Razak Khaleel A
Department of Psychology and Neuroscience Graduate Program, University of California, Riverside, Riverside, CA, United States.
Neuroscience Graduate Program, University of California, Riverside, Riverside, CA, United States.
Front Neurosci. 2020 Aug 4;14:771. doi: 10.3389/fnins.2020.00771. eCollection 2020.
Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability. Many symptoms of FXS overlap with those in autism including repetitive behaviors, language delays, anxiety, social impairments and sensory processing deficits. Electroencephalogram (EEG) recordings from humans with FXS and an animal model, the knockout (KO) mouse, show remarkably similar phenotypes suggesting that EEG phenotypes can serve as biomarkers for developing treatments. This includes enhanced resting gamma band power and sound evoked total power, and reduced fidelity of temporal processing and habituation of responses to repeated sounds. Given the therapeutic potential of the antibiotic minocycline in humans with FXS and animal models, it is important to determine sensitivity and selectivity of EEG responses to minocycline. Therefore, in this study, we examined if a 10-day treatment of adult KO mice with minocycline (oral gavage, 30 mg/kg per day) would reduce EEG abnormalities. We tested if minocycline treatment has specific effects based on the EEG measurement type (e.g., resting versus sound-evoked) from the frontal and auditory cortex of the KO mice. We show increased resting EEG gamma power and reduced phase locking to time varying stimuli as well as the 40 Hz auditory steady state response in the KO mice in the pre-drug condition. Minocycline treatment increased gamma band phase locking in response to auditory stimuli, and reduced sound-evoked power of auditory event related potentials (ERP) in KO mice compared to vehicle treatment. Minocycline reduced resting EEG gamma power in KO mice, but this effect was similar to vehicle treatment. We also report frequency band-specific effects on EEG responses. Taken together, these data indicate that sound-evoked EEG responses may serve as more sensitive measures, compared to resting EEG measures, to isolate minocycline effects from placebo in humans with FXS. Given the use of minocycline and EEG recordings in a number of neurodegenerative and neurodevelopmental conditions, these findings may be more broadly applicable in translational neuroscience.
脆性X综合征（FXS）是已知导致智力障碍的主要遗传原因。FXS的许多症状与自闭症症状重叠，包括重复行为、语言发育迟缓、焦虑、社交障碍和感觉处理缺陷。对患有FXS的人类和动物模型（基因敲除（KO）小鼠）进行的脑电图（EEG）记录显示出非常相似的表型，这表明EEG表型可作为开发治疗方法的生物标志物。这包括静息γ波段功率增强和声音诱发的总功率增强，以及时间处理保真度降低和对重复声音反应的习惯化。鉴于抗生素米诺环素对患有FXS的人类和动物模型具有治疗潜力，确定EEG对米诺环素反应的敏感性和选择性很重要。因此，在本研究中，我们研究了用米诺环素（口服灌胃，每天30 mg/kg）对成年KO小鼠进行10天治疗是否会减少EEG异常。我们测试了米诺环素治疗是否基于KO小鼠额叶和听觉皮层的EEG测量类型（例如，静息与声音诱发）产生特定效果。我们发现，在给药前状态下，KO小鼠的静息EEGγ功率增加，对随时间变化的刺激的锁相减少以及40 Hz听觉稳态反应减少。与载体处理相比，米诺环素治疗增加了KO小鼠对听觉刺激的γ波段锁相，并降低了听觉事件相关电位（ERP）的声音诱发功率。米诺环素降低了KO小鼠的静息EEGγ功率，但这种效果与载体处理相似。我们还报告了对EEG反应的频带特异性影响。综上所述，这些数据表明，与静息EEG测量相比，声音诱发的EEG反应可能是更敏感的指标，用于在患有FXS的人类中将米诺环素的效果与安慰剂区分开来。鉴于米诺环素和EEG记录在多种神经退行性和神经发育疾病中的应用，这些发现可能在转化神经科学中具有更广泛的适用性。
