Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba 278-8510, Japan.
Department of Environmental Health, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.
J Neurosci. 2021 May 19;41(20):4524-4535. doi: 10.1523/JNEUROSCI.3240-20.2021. Epub 2021 Apr 12.
Ca-dependent activator protein for secretion 2 (CAPS2) regulates dense-core vesicle (DCV) exocytosis to facilitate peptidergic and catecholaminergic transmitter release. CAPS2 deficiency in mice has mild neuronal effects but markedly impairs social behavior. Rare alterations also occur in autism spectrum disorder, although whether CAPS2-mediated release influences social behavior remains unclear. Here, we demonstrate that CAPS2 is associated with DCV exocytosis-mediated release of the social interaction modulatory peptide oxytocin (OXT). CAPS2 is expressed in hypothalamic OXT neurons and localizes to OXT nerve projection and OXT release sites, such as the pituitary. KO mice exhibited reduced plasma albeit increased hypothalamic and pituitary OXT levels, indicating insufficient release. OXT neuron-specific conditional KO supported CAPS2 function in pituitary OXT release, also affording impaired social interaction and recognition behavior that could be ameliorated by exogenous OXT administered intranasally. Thus, CAPS2 appears critical for OXT release, thereby being associated with social behavior. The role of the neuropeptide oxytocin in enhancing social interaction and social bonding behavior has attracted considerable public and neuroscientific attention. A central issue in oxytocin biology concerns how oxytocin release is regulated. Our study provides an important insight into the understanding of oxytocin-dependent social behavior from the perspective of the CAPS2-regulated release mechanism.
钙依赖的分泌激活蛋白 2（CAPS2）调节致密核心囊泡（DCV）的胞吐作用，促进肽能和儿茶酚胺递质的释放。小鼠中 CAPS2 的缺失具有轻微的神经元效应，但明显损害了社交行为。自闭症谱系障碍中也存在罕见的改变，尽管 CAPS2 介导的释放是否影响社交行为尚不清楚。在这里，我们证明 CAPS2 与 DCV 胞吐作用介导的社交互动调节肽催产素（OXT）的释放有关。CAPS2 在下丘脑 OXT 神经元中表达，并定位于 OXT 神经投射和 OXT 释放部位，如垂体。 KO 小鼠表现出血浆中 OXT 减少，尽管下丘脑和垂体中的 OXT 水平增加，表明释放不足。OXT 神经元特异性条件性 KO 支持 CAPS2 在垂体 OXT 释放中的功能，也导致社交互动和识别行为受损，通过鼻腔内给予外源性 OXT 可以改善这种情况。因此，CAPS2 似乎对 OXT 释放至关重要，从而与社交行为有关。神经肽催产素在增强社交互动和社交联系行为方面的作用引起了公众和神经科学界的极大关注。催产素生物学中的一个核心问题是如何调节催产素的释放。我们的研究从 CAPS2 调节的释放机制的角度提供了对理解催产素依赖性社交行为的重要见解。
