DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release.
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.
Chen
Xiao-Wei
XW
Institute of Molecular Medicine and 2State Key Laboratory of Biomembrane Engineering, Peking University, Beijing 100871, China.
Feng
Ya-Qin
YQ
Hao
Chan-Juan
CJ
Guo
Xiao-Li
XL
He
Xin
X
Zhou
Zhi-Yong
ZY
Guo
Ning
N
Huang
Hong-Ping
HP
Xiong
Wei
W
Zheng
Hui
H
Zuo
Pan-Li
PL
Zhang
Claire Xi
CX
Li
Wei
W
Zhou
Zhuan
Z
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
D002352:Carrier Proteins; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D018377:Neurotransmitter Agents