Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia.
Schizophrenia (SCZ) is a complex trait with a high heritability. The DTNBP1 gene (encoding dysbindin) is one of the leading susceptible genes of SCZ. This risk gene has been reported to be associated with clinical symptoms such as negative symptoms and cognitive deficits. Although reduction of dysbindin expression in schizophrenic brain tissue has been reported, how this contributes to its symptomatology remains uncertain. The sandy (sdy) mouse, which harbors a spontaneously occurring deletion in the Dtnbp1 gene and expresses no dysbindin protein, provides a unique tool to study the role of dysbindin in SCZ. Our recent findings reveal that the sdy mice exhibit specific defects of neurosecretion and synaptic morphology in hippocampal neurons. We here further described that sdy manifested schizophrenia-like behaviors such as social withdrawal and cognitive deficits. In sdy hippocampus, the steady-state level of snapin (a SNAP25-binding protein and a synaptic priming regulator) was reduced due to loss of dysbindin. We further characterized that a 30-residue peptide in dysbindin (90-119 amino acids) mediated the interaction with snapin. Our results suggest that the destabilization of snapin in sdy mice may lead to abnormal neurotransmission and therefore abnormal behaviors. This further defines the sdy mutant as a potential model in schizophrenia research.
Feng
Ya-Qin
YQ
Key Laboratory of Molecular and Developmental Biology, Institute of Genetics & Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
Zhou
Zhi-Yong
ZY
He
Xin
X
Wang
Hao
H
Guo
Xiao-Li
XL
Hao
Chan-Juan
CJ
Guo
Yang
Y
Zhen
Xue-Chu
XC
Li
Wei
W
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D003072:Cognition Disorders / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D012559:Schizophrenia / Q000503:physiopathology*; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000502:physiology
D002352:Carrier Proteins; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; C498451:Snapin protein, mouse; D033921:Vesicular Transport Proteins