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.

精神分裂症易感基因dystrobrevin-binding protein 1 ( DTNBP1 )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DTNBP1丢失可能导致突触前小泡传递不足，这与多种精神疾病有关。然而，dysbindin 介导的突触小泡传递的功能机制尚未得到系统研究。在这项研究中，我们在 Held 突触的花萼中进行了电生理记录。我们发现兴奋性突触后电流 (EPSC) 和微型 EPSC (mEPSC) 振幅在dysbindin 缺陷型突触中没有变化，但在高频刺激期间容易释放池 (RRP) 大小和钙依赖性囊泡补充受到影响。此外，dysbindin 丢失伴随着 Munc18-1 和 snapin 表达水平的轻微下降，这与高频刺激下的囊泡启动和突触稳态有关。一起，我们推断，dysbindin 直接与 Munc18-1 和 snapin 相互作用以介导钙依赖性 RRP 补充。Dysbindin 损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。