Auditory processing enhancements in the TS2-neo mouse model of Timothy Syndrome, a rare genetic disorder associated with autism spectrum disorders.
Auditory processing enhancements in the TS2-neo mouse model of Timothy Syndrome, a rare genetic disorder associated with autism spectrum disorders.
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DOI：
10.1007/s41252-017-0029-1
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发表时间：
2017-09
影响因子：
--
通讯作者：
Holly Fitch R
中科院分区：
文献类型：
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作者：
Rendall AR;Ford AL;Perrino PA;Holly Fitch R
Timothy综合征（TS）是一种罕见的遗传性疾病，由编码电压门控l型Ca2+通道（Cav1.2）的CACNA1C基因8A外显子的单个从头错配突变引起。TS与心律失常、自闭症谱系障碍（ASDs）和神经功能障碍（如语言障碍、癫痫发作和智力残疾）密切相关。在含有新霉素耐药盒的l型钙通道中，培养了具有异质TS2 （G406R）突变的基因工程敲入小鼠，以研究asd样行为。该小鼠模型（TS2-neo）为我们研究钙通道失活和钙信号在脑发育和ASD中的作用提供了一个平台。本研究的目的是通过评估TS2-neo小鼠在各种行为范式上的表现来表征它们的行为特征，包括复制支持TS2-neo作为研究asd样行为的有效平台的研究结果。除了研究核心的社会和重复异常外，我们还试图关注听觉领域的基本感知处理。结果表明，在该小鼠模型中，Cav1.2失活的缺失会导致异常的社交和重复行为以及感觉运动学习不良。此外，TS2-neo小鼠在短时间声刺激下的嵌入式音调和无声间隙识别任务中都表现出优异的表现。这些发现与在ASD临床人群中观察到的低水平听觉增强相似。此外，突变小鼠在一些白质束和内侧膝状核（MGN）中发现结构异常。这些发现的共同出现表明，异常的MGN形态可能与ASD中所见的听觉加工表型增强有关。
Timothy syndrome (TS) is a rare genetic disorder caused by a single de novo missense mutation to the 8A exon of CACNA1C gene, which codes for the voltage-gated L-type Ca2+channel (Cav1.2). TS is strongly associated with cardiac arrthytmias, autism spectrum disorders (ASDs), and neurological dysfunction such as language impairments, seizures, and intellectual disability. A genetically engineered knock-in mouse with a heterogeneous TS2 (G406R) mutation in the L-type calcium channel containing a neomycin resistance cassette was developed to study ASD-like behaviors. This mouse model (TS2-neo) provides us with a platform to investigate the role of calcium channel inactivation and calcium signaling related to brain development and ASD. The purpose of the current study was to behaviorally characterize TS2-neo mice by assessing their performance on a wide variety of behavioral paradigms, including replication of findings that support the TS2-neo as a valid platform for studying ASD-like behavior. In addition to examining core social and repetitive anomalies, we sought to focus on basic perceptual processing in the auditory domain. Results indicate that the loss of Cav1.2 inactivation in this mouse model results in deviant social and repetitive behaviors as well as poor sensorimotor learning. Additionally, TS2-neo mice display superior performance on both an embedded tone and silent gap discrimination task for short-duration acoustic stimuli. These findings parallel the low-level auditory enhancements observed within the ASD clinical population. Additionally, structural anomalies were seen for mutant mice in some white matter tracts and in the medial geniculate nucleus (MGN). Co-occurrence of these findings suggests that aberrant MGN morphology may be related to enhanced auditory processing phenotype as seen in ASD.