Section on Integrative Neuroimaging, National Institute of Mental Health, NIH, DHHS, Bethesda, MD 20892-1365, USA.
Mol Psychiatry. 2013 Jun;18(6):713-20. doi: 10.1038/mp.2012.187. Epub 2013 Jan 15.
A Val(66)Met single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene impairs activity-dependent BDNF release in cultured hippocampal neurons and predicts impaired memory and exaggerated basal hippocampal activity in healthy humans. Several clinical genetic association studies along with multi-modal evidence for hippocampal dysfunction in schizophrenia indirectly suggest a relationship between schizophrenia and genetically determined BDNF function in the hippocampus. To directly test this hypothesized relationship, we studied 47 medication-free patients with schizophrenia or schizoaffective disorder and 74 healthy comparison individuals with genotyping for the Val(66)Met SNP and [(15)O]H(2)O positron emission tomography (PET) to measure resting and working memory-related hippocampal regional cerebral blood flow (rCBF). In patients, harboring a Met allele was associated with significantly less hippocampal rCBF. This finding was opposite to the genotype effect seen in healthy participants, resulting in a significant diagnosis-by-genotype interaction. Exploratory analyses of interregional resting rCBF covariation revealed a specific and significant diagnosis-by-genotype interaction effect on hippocampal-prefrontal coupling. A diagnosis-by-genotype interaction was also found for working memory-related hippocampal rCBF change, which was uniquely attenuated in Met allele-carrying patients. Thus, both task-independent and task-dependent hippocampal neurophysiology accommodates a Met allelic background differently in patients with schizophrenia than in control subjects. Potentially consistent with the hypothesis that cellular sequelae of the BDNF Val(66)Met SNP interface with aspects of schizophrenic hippocampal and frontotemporal dysfunction, these results warrant future investigation to understand the contributions of unique patient trait or state variables to these robust interactions.
脑源性神经营养因子 (BDNF) 基因中的 Val(66)Met 单核苷酸多态性 (SNP) 会损害培养的海马神经元中依赖活动的 BDNF 释放，并预测健康人群的记忆受损和基底海马活动过度。几项临床遗传关联研究以及精神分裂症中海马功能障碍的多模态证据间接表明，精神分裂症与海马中遗传决定的 BDNF 功能之间存在关系。为了直接检验这种假设的关系，我们研究了 47 名未服用药物的精神分裂症或分裂情感障碍患者和 74 名健康对照个体，对 Val(66)Met SNP 进行基因分型，并进行 [(15)O]H(2)O 正电子发射断层扫描 (PET) 以测量静息和工作记忆相关的海马区域脑血流 (rCBF)。在患者中，携带 Met 等位基因与海马 rCBF 显著减少相关。这一发现与健康参与者中观察到的基因型效应相反，导致诊断-基因型相互作用显著。对静息 rCBF 区域间协方差的探索性分析显示，在海马-前额叶偶联方面存在特定且显著的诊断-基因型相互作用效应。还发现了与工作记忆相关的海马 rCBF 变化的诊断-基因型相互作用，该作用在携带 Met 等位基因的患者中被唯一减弱。因此，在精神分裂症患者中，任务独立和任务依赖的海马神经生理学对 Met 等位基因背景的适应方式与对照受试者不同。这些结果与 BDNF Val(66)Met SNP 的细胞后果与精神分裂症海马和额颞叶功能障碍的某些方面相互作用的假设潜在一致，值得进一步研究以了解独特的患者特征或状态变量对这些强大相互作用的贡献。
