title: DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release.
abstract: 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.
authors.affiliation: Institute of Molecular Medicine and 2State Key Laboratory of Biomembrane Engineering, Peking University, Beijing 100871, China.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Chen
authors.forename: Ya-Qin
authors.initials: YQ
authors.lastname: Feng
authors.forename: Chan-Juan
authors.initials: CJ
authors.lastname: Hao
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Guo
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Zhou
authors.forename: Ning
authors.initials: N
authors.lastname: Guo
authors.forename: Hong-Ping
authors.initials: HP
authors.lastname: Huang
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Pan-Li
authors.initials: PL
authors.lastname: Zuo
authors.forename: Claire Xi
authors.initials: CX
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D019439:Chromaffin Cells / Q000378:metabolism; D004195:Disease Models, Animal; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D004563:Electrochemistry / Q000379:methods; D017353:Gene Deletion; D007700:Kinetics; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011336:Probability; D012559:Schizophrenia / Q000235:genetics*; D013569:Synapses / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D018377:Neurotransmitter Agents