Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma 371-8511, Japan.
Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):21104-9. doi: 10.1073/pnas.1210055109. Epub 2012 Dec 3.
Ca(2)(+)-dependent activator protein for secretion 2 (CAPS2 or CADPS2) potently promotes the release of brain-derived neurotrophic factor (BDNF). A rare splicing form of CAPS2 with deletion of exon3 (dex3) was identified to be overrepresented in some patients with autism. Here, we generated Caps2-dex3 mice and verified a severe impairment in axonal Caps2-dex3 localization, contributing to a reduction in BDNF release from axons. In addition, circuit connectivity, measured by spine and interneuron density, was diminished globally. The collective effect of reduced axonal BDNF release during development was a striking and selective repertoire of deficits in social- and anxiety-related behaviors. Together, these findings represent a unique mouse model of a molecular mechanism linking BDNF-mediated coordination of brain development to autism-related behaviors and patient genotype.
钙（2）（+）依赖性分泌蛋白 2（CAPS2 或 CADPS2）可强力促进脑源性神经营养因子（BDNF）的释放。一种罕见的 CAPS2 剪接形式，外显子 3（dex3）缺失，在一些自闭症患者中过度表达。在这里，我们生成了 Caps2-dex3 小鼠，并证实了轴突 Caps2-dex3 定位严重受损，导致 BDNF 从轴突释放减少。此外，通过棘突和中间神经元密度测量的回路连接性整体减少。发育过程中轴突 BDNF 释放减少的综合影响是社交和焦虑相关行为中明显而选择性的缺陷谱。总之，这些发现代表了一种独特的小鼠模型，该模型将 BDNF 介导的脑发育协调与自闭症相关行为和患者基因型联系起来的分子机制。
