Learning delays in a mouse model of Autism Spectrum Disorder.
Learning delays in a mouse model of Autism Spectrum Disorder.
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DOI：
10.1016/j.bbr.2016.02.006
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发表时间：
2016-04-15
影响因子：
2.7
通讯作者：
Fitch RH
中科院分区：
文献类型：
--
作者：
Rendall AR;Truong DT;Fitch RH
自闭症谱系障碍（ASD）是一种异质性神经发育障碍，其核心症状是非典型的社会互动和重复行为。据报道，ASD患者在多感觉整合方面存在困难，这可能会破坏高阶认知能力，如学习和社交。感觉信息整合的障碍反过来又反映了跨通道白色物质连接的减少。此外，ASD的遗传贡献似乎很强，遗传率估计高达90%。然而，没有一个单一的基因被确定，超过1,000个风险基因已被报道。其中一个基因-接触素相关样蛋白2（CNTNAP 2）-首先与特定语言障碍有关，最近与ASD有关。CNTNAP 2编码调节突触信号传递的细胞粘附蛋白。为了更好地理解ASD的行为和生物学基础机制，用啮齿动物同源物Cntnap 2的基因敲除（KO）创建转基因小鼠模型。对这只老鼠的初步研究显示，它的社会交往能力差，行为持续，发声减少--所有这些都与人类ASD症状非常相似。Cntnap 2 KO小鼠也显示髓鞘形成异常，与ASD的低连接模型一致。目前的研究旨在进一步评估这种小鼠模型的行为表型，重点是学习和记忆。在4/8径向臂水迷宫上连续14天测试Cntnap 2 KO和野生型小鼠。使用2 × 14重复测量ANOVA独立评估错误评分（总分、工作记忆、参考记忆、初始和重复参考记忆）、潜伏期和平均转角。结果表明，Cntnap 2基因敲除小鼠在任务获得期间表现出工作记忆和参考记忆的显著缺陷。在保留期间（即，在误差渐近线之后），Cntnap 2 KO小鼠与野生型小鼠相比表现更好。这些研究结果表明，CNTNAP 2可能会影响神经系统的发展，重要的学习和跨模态整合，这一功能的中断可能与ASD的学习延迟。
Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder with core symptoms of atypical social interactions and repetitive behaviors. It has also been reported that individuals with ASD have difficulty with multisensory integration, and this may disrupt higher-order cognitive abilities such as learning and social communication. Impairments in the integration of sensory information could in turn reflect diminished cross-modal white matter connectivity. Moreover, the genetic contribution in ASD appears to be strong, with heritability estimates as high as 90%. However, no single gene has been identified, and over 1,000 risk genes have been reported. One of these genes -- contactin-associated-like-protein 2 (CNTNAP2) -- was first associated with Specific Language Impairment, and more recently has been linked to ASD. CNTNAP2 encodes a cell adhesion protein regulating synaptic signal transmission. To better understand the behavioral and biological underlying mechanisms of ASD, a transgenic mouse model was created with a genetic knockout (KO) of the rodent homolog Cntnap2. Initial studies on this mouse revealed poor social interactions, behavioral perseveration, and reduced vocalizations -- all strongly resembling human ASD symptoms. Cntnap2 KO mice also show abnormalities in myelin formation, consistent with a hypo-connectivity model of ASD. The current study was designed to further assess the behavioral phenotype of this mouse model, with a focus on learning and memory. Cntnap2 KO and wild-type mice were tested on a 4/8 radial arm water maze for 14 consecutive days. Error scores (total, working memory, reference memory, initial and repeated reference memory), latency and average turn angle were independently assessed using a 2 × 14 repeated measures ANOVA. Results showed that Cntnap2 KO mice exhibited significant deficits in working and reference memory during the acquisition period of the task. During the retention period (i.e., after asymptote in errors), Cntnap2 KO mice performed comparably to wild-type mice. These findings suggest that CNTNAP2 may influence the development of neural systems important to learning and cross-modal integration, and that disruption of this function could be associated with delayed learning in ASD.