Thomas Alexia M, Schwartz Michael D, Saxe Michael D, Kilduff Thomas S
Biosciences Division, Center for Neuroscience, SRI International, Menlo Park, CA.
Pharma Research and Early Development, Neuroscience, Ophthalmology and Rare Disease DTA, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Sleep. 2017 Jan 1;40(1). doi: 10.1093/sleep/zsw026.
Although recent innovations have enabled modification of the rat genome, it is unclear whether enhanced utility of rodents as human disease models will result. We compared electroencephalogram (EEG) and behavioral phenotypes of rats and mice with homozygous deletion of Cntnap2, a gene associated with cortical dysplasia-focal epilepsy (CDFE) and autism spectrum disorders (ASD).
Male contactin-associated protein-like 2 (Cntnap2) knockout (KO) and wild-type (WT) rats and male Cntnap2 KO and WT mice were implanted with telemeters to record EEG, electromyogram, body temperature, and locomotor activity. Animals were subjected to a test battery for ASD-related behaviors, followed by 24-hr EEG recordings that were analyzed for sleep-wake parameters and subjected to spectral analysis.
Cntnap2 KO rats exhibited severe motor seizures, hyperactivity, and increased consolidation of wakefulness and REM sleep. By contrast, Cntnap2 KO mice demonstrated absence seizure-like events, hypoactivity, and wake fragmentation. Although seizures observed in Cntnap2 KO rats were more similar to those in CDFE patients than in KO mice, neither model fully recapitulated the full spectrum of disease symptoms. However, KOs in both species had reduced spectral power in the alpha (9-12 Hz) range during wake, suggesting a conserved EEG biomarker.
Deletion of Cntnap2 impacts similar behaviors and EEG measures in rats and mice, but with profound differences in nature and phenotypic severity. These observations highlight the importance of cross-species comparisons to understand conserved gene functions and the limitations of single- species models to provide translational insights relevant to human diseases.
尽管最近的创新技术已能够对大鼠基因组进行改造，但尚不清楚啮齿动物作为人类疾病模型的效用是否会因此得到增强。我们比较了纯合缺失Cntnap2基因的大鼠和小鼠的脑电图（EEG）及行为表型，Cntnap2基因与皮质发育异常 - 局灶性癫痫（CDFE）和自闭症谱系障碍（ASD）相关。
给雄性接触蛋白相关蛋白样2（Cntnap2）基因敲除（KO）大鼠和野生型（WT）大鼠以及雄性Cntnap2基因敲除小鼠和野生型小鼠植入遥测器，以记录脑电图、肌电图、体温和运动活动。对动物进行一系列与ASD相关行为的测试，随后进行24小时脑电图记录，分析睡眠 - 觉醒参数并进行频谱分析。
Cntnap2基因敲除大鼠表现出严重的运动性癫痫发作、多动，以及清醒和快速眼动睡眠巩固增加。相比之下，Cntnap2基因敲除小鼠表现出失神发作样事件、活动减少和清醒片段化。虽然Cntnap2基因敲除大鼠中观察到的癫痫发作比基因敲除小鼠中的更类似于CDFE患者中的癫痫发作，但两种模型均未完全重现疾病症状的全貌。然而，两个物种的基因敲除动物在清醒时α（9 - 12赫兹）范围内的频谱功率均降低，表明存在一种保守的脑电图生物标志物。
Cntnap2基因的缺失对大鼠和小鼠的类似行为和脑电图测量有影响，但在性质和表型严重程度上存在显著差异。这些观察结果突出了跨物种比较对于理解保守基因功能的重要性，以及单物种模型在提供与人类疾病相关的转化见解方面的局限性。
