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

Han Hu; Xuefeng Wang; Chao Li; Yang Li; Junfeng Hao; Yuanli Zhou; Xiaopeng Yang; Peihua Chen; Xuefeng Shen; Shuli Zhang

doi:10.1016/j.neuroscience.2020.10.020

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

Neuroscience. 2021 Jan 1:452:138-152. doi: 10.1016/j.neuroscience.2020.10.020. Epub 2020 Nov 10.

Authors

Han Hu¹, Xuefeng Wang¹, Chao Li¹, Yang Li¹, Junfeng Hao², Yuanli Zhou², Xiaopeng Yang², Peihua Chen³, Xuefeng Shen⁴, Shuli Zhang⁵

Affiliations

¹ State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
³ State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, CAS, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China. Electronic address: ph.chen@siat.ac.cn.
⁴ State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, CAS, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China. Electronic address: xf.shen@siat.ac.cn.
⁵ State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: shulizhang@ibp.ac.cn.

PMID: 33186610
DOI: 10.1016/j.neuroscience.2020.10.020

Abstract

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.

Keywords: calyx of Held; cognitive impairment; dysbindin; high-frequency stimulation; neurotransmission.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dysbindin / genetics*
Dystrophin-Associated Proteins / metabolism
Humans
Schizophrenia* / genetics
Synapses / metabolism
Synaptic Transmission
Synaptic Vesicles* / metabolism

Substances

DTNBP1 protein, human
Dysbindin
Dystrophin-Associated Proteins