Loss of Dysbindin Implicates Synaptic Vesicle Replenishment Dysregulation as a Potential Pathogenic Mechanism in Schizophrenia
Loss of Dysbindin Implicates Synaptic Vesicle Replenishment Dysregulation as a Potential Pathogenic Mechanism in Schizophrenia
复制标题
Dysbindin 的缺失表明突触小泡补充失调是精神分裂症的潜在致病机制
DOI：
10.1016/j.neuroscience.2020.10.020
复制
发表时间：
2021-01-01
期刊：
影响因子：
3.3
通讯作者：
Zhang, Shuli
中科院分区：
文献类型：
--
作者：
Hu, Han;Wang, Xuefeng;Zhang, Shuli
精神分裂症易感基因，dystrobrevin结合蛋白1（DTNBP 1），编码dysbindin蛋白，并介导正常受试者的神经传递和神经发育。功能研究表明，DTNBP 1缺失可能导致突触前囊泡传递缺陷，这与多种精神疾病有关。然而，dysbindin介导的突触囊泡传递的功能机制尚未得到系统的研究。在这项研究中，我们进行了电生理记录在萼举行的突触。我们发现，兴奋性突触后电流（EPSC）和微型EPSC（mEPSC）的幅度在dysbindin缺陷的突触不变，但容易释放池（RRP）的大小和钙依赖性囊泡的补充在高频刺激的影响。此外，dysbindin的损失伴随着Munc 18 -1和snapin表达水平的轻微下降，这与小泡启动和突触稳态高频刺激下。总之，我们推断dysbindin直接与Munc 18 -1和snapin相互作用以介导钙依赖性RRP补充。Dysbindin丢失可能导致高频刺激期间RRP补充失调，可能导致精神分裂症的认知障碍。(C)2020年IBRO。由爱思唯尔有限公司出版。保留所有权利。
The schizophrenia-susceptibility gene, dystrobrevin-binding protein 1 (DTNBP1), encodes the dysbindin protein and mediates neurotransmission and neurodevelopment in normal subjects. Functional studies show that DTNBP1 loss may cause deficient presynaptic vesicle transmission, which is related to multiple psychiatric disorders. However, the functional mechanism of dysbindin-mediated synaptic vesicle transmission has not been investigated systematically. In this study, we performed electrophysiological recordings in calyx of Held synapses. We found that excitatory postsynaptic current (EPSC) and miniature EPSC (mEPSC) amplitudes were unchanged in dysbindin-deficient synapses, but readily releasable pool (RRP) size and calcium dependent vesicle replenishment were affected during high-frequency stimulation. Moreover, dysbindin loss accompanied slightly decreases in Munc18-1 and snapin expression levels, which are associated with vesicle priming and synaptic homeostasis under high-frequency stimulation. Together, we inferred that dysbindin directly interacts with Munc18-1 and snapin to mediate calcium dependent RRP replenishment. Dysbindin loss may lead to RRP replenishment dysregulation during high-frequency stimulation, potentially causing cognitive impairment in schizophrenia. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.