Resistance to change and vulnerability to stress: autistic-like features of GAP43-deficient mice.
Resistance to change and vulnerability to stress: autistic-like features of GAP43-deficient mice.
复制标题
DOI：
10.1111/j.1601-183x.2010.00638.x
复制
发表时间：
2010-11
期刊：
影响因子：
--
通讯作者：
McCasland JS
中科院分区：
文献类型：
--
作者：
Zaccaria KJ;Lagace DC;Eisch AJ;McCasland JS
目前迫切需要自闭症谱系障碍（ASD）的动物模型，以了解潜在的病理学，并促进新疗法的开发和测试。突触生长相关蛋白43（GAP 43）最近被确定为自闭症候选基因的兴趣。我们之前的研究表明，缺乏一个GAP 43等位基因（GAP 43（+/−））的小鼠的许多大脑异常与ASD的无序连接理论一致。因此，我们假设GAP 43（+/−）小鼠至少会表现出一些类似自闭症的行为。我们发现，与野生型（+/+）同窝出生的小鼠相比，GAP 43（+/−）小鼠表现出对变化的抵抗力，这与ASD的诊断标准之一一致。GAP 43（+/−）小鼠也表现出压力诱导的行为退缩和焦虑，正如许多自闭症患者所见。此外，GAP 43（+/−）小鼠和（+/+）同窝出生的小鼠都表现出低社会接近性和缺乏对社会新奇感的偏好，这与ASD的另一个诊断标准一致。这种低社交性可能是由于混合的C57 BL/6 J 129 S3/SvImJ背景。我们的结论是，GAP 43缺陷导致自闭症样行为的发展。由于这些行为发生在一只显示无序连接的小鼠中，我们建议未来对这只小鼠的解剖和功能研究可能有助于揭示这些特定行为的潜在机制。在这些研究中，菌株特异性的低社交性可能是有利的，为研究GAP 43介导的对变化的抵抗力和对压力的脆弱性的缺陷创造了更像自闭症的环境。
There is an urgent need for animal models of autism spectrum disorder (ASD) to understand the underlying pathology and facilitate development and testing of new treatments. The synaptic growth-associated protein-43 (GAP43) has recently been identified as an autism candidate gene of interest. Our previous studies show many brain abnormalities in mice lacking one allele for GAP43 (GAP43 (+/−)) that are consistent with the disordered connectivity theory of ASD. Thus, we hypothesized that GAP43 (+/−) mice would demonstrate at least some autistic-like behaviors. We found that GAP43 (+/−) mice, relative to wild-type (+/+) littermates, displayed resistance to change, consistent with one of the diagnostic critera for ASD. GAP43 (+/−) mice also displayed stress-induced behavioral withdrawal and anxiety, as seen in many autistic individuals. In addition, both GAP43 (+/−) mice and (+/+) littermates demonstrated low social approach and lack of preference for social novelty, consistent with another diagnostic criterion for ASD. This low sociability is likely due to the mixed C57BL/6J 129S3/SvImJ background. We conclude that GAP43 deficiency leads to the development of a subset of autistic-like behaviors. Since these behaviors occur in a mouse that displays disordered connectivity, we propose that future anatomical and functional studies in this mouse may help uncover underlying mechanisms for these specific behaviors. Strain-specific low sociability may be advantageous in these studies, creating a more autistic-like environment for study of the GAP43-mediated deficits of resistance to change and vulnerability to stress.