DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release

作者：Chen, Xiao-Wei; Feng, Ya-Qin; Hao, Chan-Juan; Guo, Xiao-Li; He, Xin; Zhou, Zhi-Yong; Guo, Ning; Huang, Hong-Ping; Xiong, Wei; Zheng, Hui; Zuo, Pan-Li; Zhang, Claire Xi; Li, Wei^*; Zhou, Zhuan

来源：The Journal of Cell Biology, 2008, 181(5): 791-801.

DOI：10.1083/jcb.200711021

• ADRENAL CHROMAFFIN CELLS
• ORGANELLES COMPLEX-1 BLOC-1
• ROOT GANGLION NEURONS
• DENSE-CORE VESICLES
• HIPPOCAMPAL-FORMATION
• QUANTAL SIZE
• DYSBINDIN DTNBP1
• PROTEIN
• EXOCYTOSIS
• SNAPIN

Schizophrenia is one of the most debilitating neuropsychiatric disorders, affecting 0.5-1.0% of the population worldwide. Its pathology, attributed to defects in synaptic transmission, remains elusive. The dystrobrevin-binding protein 1 (DTNBP1) gene, which encodes a coiled-coil protein, dysbindin, is a major susceptibility gene for schizophrenia. Our previous results have demonstrated that the sandy (sdy) mouse harbors a spontaneously occurring deletion in the DTNBP1 gene and expresses no dysbindin protein (Li, W., Q. Zhang, N. Oiso, E. K. Novak, R. Gautam, E. P. O'Brien, C. L. Tinsley, D. J. Blake, R. A. Spritz, N. G. Copeland, et al. 2003. Nat. Genet. 35: 84-89). Here, using amperometry, whole-cell patch clamping, and electron microscopy techniques, we discovered specific defects in neurosecretion and vesicular morphology in neuroendocrine cells and hippocampal synapses at the single vesicle level in sdy mice. These defects include larger vesicle size, slower quantal vesicle release, lower release probability, and smaller total population of the readily releasable vesicle pool. These findings suggest that dysbindin functions to regulate exocytosis and vesicle biogenesis in endocrine cells and neurons. Our work also suggests a possible mechanism in the pathogenesis of schizophrenia at the synaptic level.

• 出版日期2008-6-2
• 单位中国科学院遗传与发育生物学研究所; 北京大学