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

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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.