Reduced axonal localization of a Caps2 splice variant impairs axonal release of BDNF and causes autistic-like behavior in mice
Reduced axonal localization of a Caps2 splice variant impairs axonal release of BDNF and causes autistic-like behavior in mice
复制标题
DOI：
10.1073/pnas.1210055109
复制
发表时间：
2012-12-18
影响因子：
11.1
通讯作者：
Furuichi, Teiichi
中科院分区：
文献类型：
--
作者：
Sadakata, Tetsushi;Shinoda, Yo;Furuichi, Teiichi
Ca 2+依赖性分泌激活蛋白2（CAPS 2或CADPS 2）有效促进脑源性神经营养因子（BDNF）的释放。一种罕见的CAPS 2外显子3缺失（dex 3）剪接形式在一些自闭症患者中被发现过度表达。在这里，我们产生了Caps 2-dex 3小鼠，并验证了轴突Caps 2-dex 3定位的严重损伤，有助于减少BDNF从轴突释放。此外，通过脊柱和中间神经元密度测量的电路连接性在全球范围内减少。在发育过程中减少轴突BDNF释放的集体效应是一个引人注目的和选择性的赤字在社会和焦虑相关的行为。总之，这些发现代表了一种独特的小鼠模型，该模型的分子机制将BDNF介导的大脑发育协调与自闭症相关行为和患者基因型联系起来。
Ca2+-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.