Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Cell. 2011 Sep 30;147(1):235-46. doi: 10.1016/j.cell.2011.08.040.
Although many genes predisposing to autism spectrum disorders (ASD) have been identified, the biological mechanism(s) remain unclear. Mouse models based on human disease-causing mutations provide the potential for understanding gene function and novel treatment development. Here, we characterize a mouse knockout of the Cntnap2 gene, which is strongly associated with ASD and allied neurodevelopmental disorders. Cntnap2(-/-) mice show deficits in the three core ASD behavioral domains, as well as hyperactivity and epileptic seizures, as have been reported in humans with CNTNAP2 mutations. Neuropathological and physiological analyses of these mice before the onset of seizures reveal neuronal migration abnormalities, reduced number of interneurons, and abnormal neuronal network activity. In addition, treatment with the FDA-approved drug risperidone ameliorates the targeted repetitive behaviors in the mutant mice. These data demonstrate a functional role for CNTNAP2 in brain development and provide a new tool for mechanistic and therapeutic research in ASD.
尽管已经确定了许多导致自闭症谱系障碍 (ASD) 的基因，但生物学机制仍不清楚。基于人类致病突变的小鼠模型为理解基因功能和新的治疗方法的发展提供了可能。在这里，我们描述了 Cntnap2 基因敲除小鼠的特征，该基因与 ASD 和相关神经发育障碍密切相关。Cntnap2(-/-) 小鼠在三个核心 ASD 行为领域表现出缺陷，以及多动和癫痫发作，这在具有 CNTNAP2 突变的人类中已有报道。在癫痫发作前对这些小鼠进行神经病理学和生理学分析显示出神经元迁移异常、中间神经元数量减少和异常的神经元网络活动。此外，使用美国食品和药物管理局批准的药物利培酮治疗可改善突变小鼠的靶向重复行为。这些数据表明 CNTNAP2 在大脑发育中具有功能作用，并为 ASD 的机制和治疗研究提供了新的工具。
