Recognition deficits in mice carrying mutations of genes encoding BLOC-1 subunits pallidin or dysbindin.
Recognition deficits in mice carrying mutations of genes encoding BLOC-1 subunits pallidin or dysbindin.
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携带编码 BLOC-1 亚基 pallidin 或 Dysbindin 基因突变的小鼠的识别缺陷。
DOI：
10.1111/gbb.12240
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Karlsgodt,KH
中科院分区：
文献类型：
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作者：
Spiegel,S;Chiu,A;James,AS;Jentsch,JD;Karlsgodt,KH
许多研究表明，编码dystrobrevin结合蛋白或结合素障碍的基因DTNBP1是精神分裂症的候选风险基因，尽管这种关系仍然存在一些争议。异常结合蛋白的变异及其在染色体6p上的位置与认知过程有关，包括依赖于谷氨酸和多巴胺能相互作用的复杂系统。异常结合蛋白是构成溶酶体相关细胞器复合体1(BLOC-1)生物发生的7个蛋白质亚基之一。在BLOC-1中的另一个基因pallidin零突变的小鼠中，dybindin蛋白的水平较低，而delbindin基因零突变的小鼠中pallidin的蛋白水平较低，这表明必须存在多个亚单位蛋白才能形成功能上的寡聚复合体。此外，苍白素和结合素在小鼠和人脑中的分布模式相似。在这里，我们调查了苍白和异常结合蛋白在基因表达水平上的明显对应是否也在行为水平上被发现。假设导致这两种蛋白质表达不足的突变应该表现出类似的表型效应，我们使用新的对象识别任务(NORT)和社会新奇识别任务(SNRT)研究了两个菌株的识别记忆。我们发现，与野生型对照相比，任何一种基因零突变的小鼠在SNRT和NORT上都受到了损害。这些结果支持这样的结论，即与认知记忆障碍相一致的缺陷，即精神分裂症中的一种认知功能受损，是由苍白素或异常结合蛋白突变造成的，可能是通过BLOC-1表达和/或功能的退化。
Numerous studies have implicatedDTNBP1, the gene encoding dystrobrevin‐binding protein or dysbindin, as a candidate risk gene for schizophrenia, though this relationship remains somewhat controversial. Variation in dysbindin, and its location on chromosome 6p, has been associated with cognitive processes, including those relying on a complex system of glutamatergic and dopaminergic interactions. Dysbindin is one of the seven protein subunits that comprise the biogenesis of lysosome‐related organelles complex 1 (BLOC‐1). Dysbindin protein levels are lower in mice with null mutations in pallidin, another gene in the BLOC‐1, and pallidin levels are lower in mice with null mutations in the dysbindin gene, suggesting that multiple subunit proteins must be present to form a functional oligomeric complex. Furthermore, pallidin and dysbindin have similar distribution patterns in a mouse and human brain. Here, we investigated whether the apparent correspondence of pallid and dysbindin at the level of gene expression is also found at the level of behavior. Hypothesizing a mutation leading to underexpression of either of these proteins should show similar phenotypic effects, we studied recognition memory in both strains using the novel object recognition task (NORT) and social novelty recognition task (SNRT). We found that mice with a null mutation in either gene are impaired on SNRT and NORT when compared with wild‐type controls. These results support the conclusion that deficits consistent with recognition memory impairment, a cognitive function that is impaired in schizophrenia, result from either pallidin or dysbindin mutations, possibly through degradation of BLOC‐1 expression and/or function.