Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2011 Mar 1;6(3):e16886. doi: 10.1371/journal.pone.0016886.
An increasing number of studies report associations between variation in DTNBP1, a top candidate gene in schizophrenia, and both the clinical symptoms of the disorder and its cognitive deficits. DTNBP1 encodes dysbindin-1, reduced levels of which have been found in synaptic fields of schizophrenia cases. This study determined whether such synaptic reductions are isoform-specific.
METHODOLOGY/PRINCIPAL FINDINGS: Using Western blotting of tissue fractions, we first determined the synaptic localization of the three major dysbindin-1 isoforms (A, B, and C). All three were concentrated in synaptosomes of multiple brain areas, including auditory association cortices in the posterior half of the superior temporal gyrus (pSTG) and the hippocampal formation (HF). Tests on the subsynaptic tissue fractions revealed that each isoform is predominantly, if not exclusively, associated with synaptic vesicles (dysbindin-1B) or with postsynaptic densities (dysbindin-1A and -1C). Using Western blotting on pSTG (n = 15) and HF (n = 15) synaptosomal fractions from schizophrenia cases and their matched controls, we discovered that synaptic dysbindin-1 is reduced in an isoform-specific manner in schizophrenia without changes in levels of synaptophysin or PSD-95. In pSTG, about 92% of the schizophrenia cases displayed synaptic dysbindin-1A reductions averaging 48% (p = 0.0007) without alterations in other dysbindin-1 isoforms. In the HF, by contrast, schizophrenia cases displayed normal levels of synaptic dysbindin-1A, but 67% showed synaptic reductions in dysbindin-1B averaging 33% (p = 0.0256), while 80% showed synaptic reductions in dysbindin-1C averaging 35% (p = 0.0171).
CONCLUSIONS/SIGNIFICANCE: Given the distinctive subsynaptic localization of dysbindin-1A, -1B, and -1C across brain regions, the observed pSTG reductions in dysbindin-1A are postsynaptic and may promote dendritic spine loss with consequent disruption of auditory information processing, while the noted HF reductions in dysbindin-1B and -1C are both presynaptic and postsynaptic and could promote deficits in spatial working memory.
越来越多的研究报告表明，精神分裂症的顶级候选基因 DTNBP1 的变异与该疾病的临床症状及其认知缺陷都有关联。DTNBP1 编码 dysbindin-1，在精神分裂症病例的突触区域中发现其水平降低。本研究旨在确定这种突触减少是否具有同工型特异性。
方法/主要发现：我们首先使用组织部分的 Western 印迹法确定了 dysbindin-1 的三种主要同工型（A、B 和 C）的突触定位。所有三种同工型都集中在包括后上颞叶（pSTG）后部听觉联合皮质和海马结构（HF）在内的多个脑区的突触体中。对亚突触组织部分的测试表明，每种同工型主要（如果不是完全）与突触小泡（dysbindin-1B）或与突触后密度（dysbindin-1A 和 -1C）相关。我们使用 Western 印迹法对精神分裂症病例及其匹配对照的 pSTG（n=15）和 HF（n=15）突触体部分进行分析，发现突触 dysbindin-1 以同工型特异性方式减少，而突触小泡相关蛋白 95 或突触后密度-95 没有变化。在 pSTG 中，大约 92%的精神分裂症病例显示突触 dysbindin-1A 减少，平均减少 48%（p=0.0007），而其他 dysbindin-1 同工型没有改变。相比之下，HF 中的精神分裂症病例显示突触 dysbindin-1A 水平正常，但 67%的病例显示 dysbindin-1B 减少，平均减少 33%（p=0.0256），而 80%的病例显示 dysbindin-1C 减少，平均减少 35%（p=0.0171）。
结论/意义：鉴于 dysbindin-1A、-1B 和 -1C 在大脑区域中的独特亚突触定位，观察到的 pSTG 中 dysbindin-1A 的减少是突触后的，可能导致树突棘丢失，从而破坏听觉信息处理，而 HF 中 dysbindin-1B 和 -1C 的减少既是突触前的也是突触后的，可能导致空间工作记忆缺陷。
