Loss of Dysbindin Implicates Synaptic Vesicle Replenishment Dysregulation as a Potential Pathogenic Mechanism in Schizophrenia

• Published in: Neuroscience Vol. 452; pp. 138 - 152
• Main Authors: Hu, Han, Wang, Xuefeng, Li, Chao, Li, Yang, Hao, Junfeng, Zhou, Yuanli, Yang, Xiaopeng, Chen, Peihua, Shen, Xuefeng, Zhang, Shuli
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.01.2021
• Subjects: calyx of Held; cognitive impairment; dysbindin; Dysbindin - genetics; Dystrophin-Associated Proteins - metabolism; high-frequency stimulation; Humans; neurotransmission; Schizophrenia - genetics; Synapses - metabolism; Synaptic Transmission; Synaptic Vesicles - metabolism; Prns; mEPSC; high-frequency stimulation; eEPSC; SNARE; SVns; RRP; Nns; EPSC; ISI; Pr; SV; neurotransmission; Prss; SVall; SVss; calyx of Held; DTNBP1; MNTB; dysbindin; PSR; Nss; NnsH; SVslow; SVsynchronous; PNs; aCSF; cognitive impairment; NnsL; TEM
• ISSN: 0306-4522; 1873-7544; 1873-7544
• DOI: 10.1016/j.neuroscience.2020.10.020

[Display omitted] •Loss of dysbindin increases evoked vesicle release probability in calyx of Held synapses.•Loss of dysbindin reduces readily releasable pool size of calyx of Held synapses during high-frequency stimulation.•Loss of dysbindin significantly decreases normal primed vesicle numbers but don’t change superprimed vesicles numbers.•Loss of dysbindin reduces vesicle replenishment in calyx of Held synapses.•Loss of dysbindin causes reduced Munc18-1 and snapin expression in calyx of Held synapses. 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.