精神分裂症(schizophrenia)是一类遗传度较高的精神疾病，全球人群患病率为0.5—1.0%。研究表明它可能是一种突触疾病，但它的突触病理变化和突触传递异常的细节还不清楚。DTNBP1是精神分裂症主要的易感基因之一，它编码溶酶体相关细胞器生物发生复合体—1 (BLOC—1) 的亚基之一Dysbindin，参与溶酶体相关细胞器的生物发生。李巍及其合作者以前的研究已证实sdy小鼠Dtnbp1基因的缺失突变，导致该基因编码的蛋白不表达(Li，et al. Nat Genet，2003)，透射电镜观察发现sdy小鼠海马CA1区不对称突触中，突触小泡数量减少、体积变大，表明DTNBP1参与突触小泡（被认为属于一类溶酶体相关细胞器）的发生。在此基础上，利用碳纤电极安培法，全细胞膜片钳等实验技术研究嗜铬细胞和海马神经元的胞吐现象，发现sdy细胞释放池减小、小泡释放动力学减慢。提示该蛋白在突触小泡的发生、小泡递质释放的启动和融合等突触前多个环节中起重要调节作用。该项研究是由北京大学周专实验室和李巍组合作完成的。该论文发表在今年的《细胞生物学杂志》（Journal of Cell Biology）杂志上，并被该期杂志重点推荐，同时被Nature China选为中国神经科学领域Research Highlights进行报道。
DTNBP1缺失后引起的海马区递质释放的效能的减低可能是精神分裂症认知与行为异常的原因。为了证实这一点，利用sdy小鼠进行了较系统的认知与精神行为学分析，发现sdy小鼠表现为类似精神分裂症的社交退缩和认知缺陷的表型。同时在分子机制上发现，sdy小鼠的递质释放异常可能由于DTNBP1缺失后导致另一重要突触释放调节蛋白Snapin的减少有关。这些结果已发表在9月的爱思唯尔期刊《精神分裂症研究》（Schizophrenia Research）上。以上这些研究成果不仅确立了sdy小鼠是研究精神分裂症的合适动物模型，还在超微病理学、电生理学、行为学和分子机制等水平，进一步支持DTNBP1基因作为精神分裂症的易感基因的学说，为药物干预研究奠定了重要基础。
原始出处：
Schizophrenia Research，doi:10.1016/j.schres.2008.07.018，Ya-Qin Feng，Wei Li
Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia
Ya-Qin Fenga, Zhi-Yong Zhoua, Xin Hea, Hao Wanga, Xiao-Li Guoa,Chan-Juan Haoa,Yang Guob, Xue-Chu Zhenb and Wei Lia,
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.
