Charite University Medicine Berlin, Campus Mitte, Clinic for Psychiatry and Psychotherapy, 10117 Berlin, Germany.
Curr Pharm Biotechnol. 2012 Jun;13(8):1513-21. doi: 10.2174/138920112800784952.
In linkage and association studies the DTNBP1 gene has been identified as a major susceptibility gene for schizophrenia. Reduced expression of DTNBP1 was found in the hippocampus and prefrontal cortex in post mortem brains of schizophrenic patients. In vitro and animal models provide evidence that the DTNBP1 gene product dysbindin modulates the activity of the neurotransmitter glutamate in hippocampal neurons and is crucial for cell functioning and synaptogenesis. This study is the first to investigate the effects of genetic variants of DTNBP1 on the status of the glutamate system as well as neuronal integrity (N-acetylaspartate, NAA) in the hippocampus and a cortical region, the anterior cingulate cortex (ACC), in humans.
In 79 healthy subjects, the association of single nucleotide polymorphisms (SNPs) rs760665 and rs909706 with absolute concentrations of glutamate and NAA in the left hippocampus and the ACC were investigated, using proton magnetic resonance spectroscopy (MRS) at 3 Tesla and a well established quantification procedure.
Hippocampal glutamate concentration was significantly affected by genotype of rs760665 (F=4.406, df=2,p=0.016) and rs909706 (F=3.171,df=2,p=0.048). For the concentration of NAA, a weak association with rs760665 was observed in the contrast analysis. None of the metabolites measured in the ACC showed a significant connection with either genotype.
The results support a role of DTNBP1 gene variants in the glutamate neurotransmission system in the human brain at least in the hippocampus. This is compatible to growing evidence of a crucial role of glutamate in the pathobiology of schizophrenia. In addition, the weak association between DTNBP1 genotype and NAA is in line with a regulatory influence of dysbindin on synaptogenesis and neuronal survival.
在连锁和关联研究中，DTNBP1 基因已被确定为精神分裂症的主要易感基因。在精神分裂症患者死后的大脑海马体和前额叶皮层中发现 DTNBP1 的表达减少。体外和动物模型提供的证据表明，DTNBP1 基因产物 dysbindin 调节海马神经元中神经递质谷氨酸的活性，对细胞功能和突触发生至关重要。这项研究首次调查了 DTNBP1 基因的遗传变异对谷氨酸系统状态以及海马体和皮质区域（前扣带皮层，ACC）中神经元完整性（N-乙酰天门冬氨酸，NAA）的影响。
在 79 名健康受试者中，使用 3 特斯拉质子磁共振波谱（MRS）和成熟的定量程序，研究单核苷酸多态性（SNP）rs760665 和 rs909706 与左侧海马体和 ACC 中谷氨酸和 NAA 的绝对浓度之间的关联。
海马体谷氨酸浓度受 rs760665 基因型（F=4.406，df=2，p=0.016）和 rs909706 基因型（F=3.171，df=2，p=0.048）的显著影响。在对比分析中，观察到 NAA 与 rs760665 的弱关联。在 ACC 中测量的任何代谢物均与任一基因型均无显著关联。
这些结果支持 DTNBP1 基因变异在人类大脑中谷氨酸能神经传递系统中的作用，至少在海马体中如此。这与谷氨酸在精神分裂症发病机制中具有关键作用的证据相吻合。此外，DTNBP1 基因型与 NAA 之间的弱关联与 dysbindin 对突触发生和神经元存活的调节作用一致。
