Study on the molecular mechanisms underlying CAPS-mediated exocytosis of dense-core vesicles containing BDNF and catecholamine

我们发现CAPS1和CAPS2与Arf4/5相互作用，Arf4/5可能参与了跨高尔基体网络(TGN)中致密核小泡(DCV)的运输。Dex3(外显子3缺失)是一种罕见的CAPS2选择性剪接变异体，在一些自闭症患者中被发现增加。我们建立了一只表达DX3的小鼠，并证实轴突DX3定位受损，导致轴突释放BDNF减少，从而导致异常突触。Dex3小鼠在社交和焦虑行为方面也表现出缺陷，这表明Dex3可能与大脑发育和自闭症相关的行为有关。虽然CAPS1调节胰岛素的分泌，但由于CAPS1 KO小鼠的新生儿死亡，其在大脑中的功能基本上是未知的。我们建立了CAPS1条件性基因敲除小鼠，并提示CAPS1的缺失扰乱了TGN-DCV途径和BDNF的释放，这可能与糖尿病和共病抑郁症的机制有关。

We showed that CAPS1 and CAPS2 interacts with Arf4/5, which is possibly involved in dense-core vesicle (DCV) trafficking in the trans-Golgi network (TGN). Dex3 (deletion of exon3) is a rare alternative splicing CAPS2 variant which was identified to be increased in some of patients with autism. We generated a dex3-expressing mice and verified an impairment in axonal dex3 localization, contributing to a reduction in BDNF release from axons and thereby resulting in abnormal synapses. Dex3 mice also showed deficits in social and anxiety behaviors, suggesting a possible association of dex3 with brain development and behavior related to autism. Although CAPS1 regulates insulin secretion, its function in the brain is essentially unknown because of neonatal death of CAPS1 KO mice. We generated CAPS1 conditional knockout mice and suggested that loss of CAPS1 disrupts the TGN-DCV pathway and BDNF release, which may be associated with a mechanism underlying diabetes and comorbid depression.