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

¹ Institute of Molecular Medicine and ² State Key Laboratory of Biomembrane Engineering, Peking University, Beijing 100871, China
³ Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China

Correspondence to Z. Zhou: zzhou{at}pku.edu.cn; or W. Li: wli{at}genetics.ac.cn

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.

X.-W. Chen's present address is Department of Physiology, Third Military Medical University, Chongqing 400038, China.

Abbreviations used in this paper: DTNBP1, dystrobrevin-binding protein 1; HHD, half-height duration; LDCV, large dense-core vesicle; mEPSC, miniature excitatory postsynaptic current; PSD, postsynaptic density; Q, quantal size; RRP, readily releasable pool; RT, rise time; sdy, sandy; WT, wild type.

© 2008 Chen et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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