Carreño-Muñoz Maria Isabel, Chattopadhyaya Bidisha, Agbogba Kristian, Côté Valérie, Wang Siyan, Lévesque Maxime, Avoli Massimo, Michaud Jacques L, Lippé Sarah, Di Cristo Graziella
Centre de Recherche, CHU Sainte-Justine (CHUSJ), Montreal, QC H3T 1C5, Canada.
Department of Neurosciences, Université de Montréal, Montreal, QC, Canada.
Brain. 2022 Apr 18;145(2):754-769. doi: 10.1093/brain/awab329.
Amongst the numerous genes associated with intellectual disability, SYNGAP1 stands out for its frequency and penetrance of loss-of-function variants found in patients, as well as the wide range of co-morbid disorders associated with its mutation. Most studies exploring the pathophysiological alterations caused by Syngap1 haploinsufficiency in mouse models have focused on cognitive problems and epilepsy; however, whether and to what extent sensory perception and processing are altered by Syngap1 haploinsufficiency is less clear. By performing EEG recordings in awake mice, we identified specific alterations in multiple aspects of auditory and visual processing, including increased baseline gamma oscillation power, increased theta/gamma phase amplitude coupling following stimulus presentation and abnormal neural entrainment in response to different sensory modality-specific frequencies. We also report lack of habituation to repetitive auditory stimuli and abnormal deviant sound detection. Interestingly, we found that most of these alterations are present in human patients as well, thus making them strong candidates as translational biomarkers of sensory-processing alterations associated with SYNGAP1/Syngap1 haploinsufficiency.
在众多与智力障碍相关的基因中，SYNGAP1因其在患者中发现的功能丧失变体的频率和外显率，以及与其突变相关的广泛共病障碍而脱颖而出。大多数探索Syngap1单倍剂量不足在小鼠模型中引起的病理生理改变的研究都集中在认知问题和癫痫上；然而，Syngap1单倍剂量不足是否以及在多大程度上改变了感觉知觉和处理尚不清楚。通过在清醒小鼠中进行脑电图记录，我们确定了听觉和视觉处理多个方面的特定改变，包括基线伽马振荡功率增加、刺激呈现后theta/伽马相位幅度耦合增加以及对不同感觉模态特定频率的异常神经夹带。我们还报告了对重复性听觉刺激缺乏习惯化以及异常的偏差声音检测。有趣的是，我们发现这些改变中的大多数在人类患者中也存在，因此使其成为与SYNGAP1/Syngap1单倍剂量不足相关的感觉处理改变的转化生物标志物的有力候选者。
