PDF(Pubmed)
Abstract：
Dysbindin-1, a protein encoded by the schizophrenia susceptibility gene DTNBP1, is reduced in the hippocampus of schizophrenia patients. It is expressed in various cellular populations of the brain and implicated in dopaminergic and glutamatergic transmission. To investigate the impact of reduced dysbindin-1 in excitatory cells on hippocampal-associated behaviors and synaptic transmission, we developed a conditional knockout mouse model with deletion of dysbindin-1 gene in CaMKIIα expressing cells. We found that dysbindin-1 reduction in CaMKII expressing cells resulted in impaired spatial and social memories, and attenuation of the effects of glutamate N-methyl-d-asparate receptor (NMDAR) antagonist MK801 on locomotor activity and prepulse inhibition of startle (PPI). Dysbindin-1 deficiency in CaMKII expressing cells also resulted in reduced protein levels of NMDAR subunit GluN1 and GluN2B. These changes were associated with increased expression of immature dendritic spines in basiliar dendrites and abnormalities in excitatory synaptic transmission in the ventral hippocampus. These results highlight the functional relevance of dysbindin-1 in excitatory cells and its implication in schizophrenia-related pathologies.
摘要：
由精神分裂症易感基因DTNBP1编码的蛋白质Dysbindin-1在精神分裂症患者的海马中减少。它在大脑的各种细胞群体中表达，并与多巴胺能和谷氨酸能传递有关。探讨兴奋性细胞内脱结合素1减少对海马相关行为和突触传递的影响。我们在表达CaMKIIα的细胞中建立了一个条件敲除小鼠模型，其中dysbindin-1基因缺失。我们发现，在CaMKII表达细胞中，dysbindin-1的减少导致空间和社会记忆受损，以及减轻谷氨酸N-甲基-d-天冬氨酸受体（NMDAR）拮抗剂MK801对运动活性和惊吓前脉冲抑制（PPI）的影响。表达CaMKII的细胞中的Dysbindin-1缺乏也导致NMDAR亚基GluN1和GluN2B的蛋白质水平降低。这些变化与基底树突中未成熟树突棘的表达增加以及腹侧海马中兴奋性突触传递异常有关。这些结果突出了兴奋性细胞中异常结合蛋白1的功能相关性及其在精神分裂症相关病理中的意义。
