近日,美国宾西法尼亚大学医学院研究人员发现在精神分裂症死者大脑组织中二乙基溴乙酰胺受体活性显著失调。研究人员通过刺激额前皮质中的受体增加了erbB4受体活性水平,与精神分裂症患者组织中的NMDA受体活性降低一样。研究显示存在一种降低NMDA受体功能的机制,并且这种机制在精神分裂症中可能长期存在,研究结果公布在本周的《自然医学》(Nature medicine)网络版中。
精神分裂症是一种精神错乱,全球发病率大概是1%,其主要特征症状有:幻觉、妄想症和行为紊乱等。先前对精神分裂症患者大脑的研究显示其改变了额前皮质的功能、大脑的认知功能组织中心、个性表达和行为控制。
目前,全球大规模的精神分裂症遗传研究聚焦在一种神经调节蛋白——NRG1中,该蛋白似乎在决定一个人是否易患某种疾病上具有重要的作用。
研究人员使用NRG1蛋白激活二乙基溴乙酰胺受体erbB4以测试死者大脑组织中的分子反应。他们通过将磷酸分子加入受体将NRG1绑定到erbB4,进而刺激二乙基溴乙酰胺受体活性,erbB4活性便依次切断神经元中的级联分子事件。在初步比较心理健康和精神分裂症患者死者大脑组织中的神经化学物质活性之后,研究人员发现NRG1-erbB4活性在精神分裂症患者大脑中有极大的提高。
这种次级神经元受体叫做NMDA,能接收神经递质传递的信号。先前的研究表明erbB4和NMDA受体活性使得研究人员认为增强erbB4受体活性会导致NMDA受体活性降低。
低水平的NMDA受体活性被认为是导致精神分裂症症状的原因。通过用谷氨酸刺激NMDA受体,随后测量受体中磷酸化的改变,研究人员能在精神分裂症患者尸体大脑组织中追踪NMDA受体活性。
研究人员推测精神分裂症可能部分是由突簇后密度蛋白(PSD)中多种因子(遗传和后天)共同影响导致,在细胞环境中的分子之间相互作用最终导致精神分裂症症状产生。接下来的研究将集中于PSD蛋白中分子相互作用的差异上.
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By University of Pennsylvania School of Medicine, Researchers at the University of Pennsylvania School of Medicine, in collaboration with scientists at the City University of New York, have identified a striking dysregulation in neuronal receptor activity in the postmortem brain tissue from patients with schizophrenia. By stimulating receptors in the prefrontal cortex, the research team tracked heightened levels of erbB4 receptor activity, as well as decreased NMDA receptor activity in the tissue from patients with schizophrenia. Additionally, they were able to identify a relationship between these two receptor groups, suggesting a mechanism for decreased NMDA receptor function that has long been suspected in schizophrenia. The researchers report their findings in this week's advanced online issue of Nature Medicine.
Schizophrenia, a mental disorder afflicting approximately one percent of the world population, is characterized by a variety of symptoms such as: hallucinations, paranoia, disorganized behavior and the inability to experience pleasure. Previous studies of the brains of patients with schizophrenia suggest altered function in the prefrontal cortex, the brain's organizational center for cognitive function, personality expression, and behavioral control. International, large-scale genetic studies of patients with schizophrenia have pointed researchers to a gene called neuregulin 1 (NRG1), which appears to play a role in determining one's susceptibility to the disease.
Chang-Gyu Hahn, M.D., Ph.D., Assistant Professor of Psychiatry, Steven Arnold, M.D., Associate Professor of Psychiatry and Neurology, and Raquel Gur, M.D., Ph.D., Professor of Psychiatry, and colleagues at Penn, in collaboration with Hoau-Yan Wang, Ph.D., at The City University of New York, took an approach to use NRG1 protein to activate its neuronal receptor, erbB4, to measure the molecular response in postmortem brain tissue.
The binding of NRG1 to erbB4 stimulates neuronal receptor activity by adding phosphate molecules to the site of the receptor. The activation of erbB4, in turn, kicks off a cascade of molecular events within the neuron. When comparing the initial steps of neurochemical activity in postmortem brain tissue of mentally healthy patients to those with schizophrenia, the researchers discovered that NRG1-erbB4 activity was significantly greater in the brains of patients with schizophrenia.
Hahn and colleagues also studied a second neuron receptor called NMDA, which receives input from the neurotransmitter glutamate. Previous studies at other labs have demonstrated the relationship between erbB4 and NMDA receptor activity and have led researchers to believe that enhanced activity of erbB4 receptors results in a decrease in NMDA receptor activity.
Low levels of NMDA receptor activity are believed to contribute to symptoms of schizophrenia. By stimulating NMDA receptors with glutamate, and measuring the subsequent changes in phosphorylation at the receptor, Penn scientists were able to track an impairment in NMDA receptor activation in the postmortem brain tissue from patients with schizophrenia.
"The fact that our studies of the brains of patients with schizophrenia demonstrate both erbB4 receptor overactivity as well as NMDA underactivity suggests the existence of a relationship between these two receptor groups," explains Hahn. "Altered NRG1-erbB4 signaling may contribute to NMDA receptor hypofunction in schizophrenia." This finding is the first to display NMDA receptor hypofunction in the brains of patients with schizophrenia.
ErbB4 and NMDA receptors are located at the post-synaptic junction, or the chemical receiving end of the neuron. Both, erbB4 and NMDA receptors, are bound to scaffolding proteins called post-synaptic density (PSD), which can bridge receptor groups together and enhance their interactions.
"PSD proteins can act like a raft in the ocean," explains Hahn. "Just as holding onto a raft increases one's chance of survival, by binding onto PSD proteins, NMDA and erbB4 receptors can enhance their activity."
Hahn hypothesizes that schizophrenia may be, in part, caused by the convergence of multiple factors (both genetic and epigenetic) at the PSD, which, in turn, alters the interaction of the molecules in the cellular environment, resulting in the symptoms of schizophrenia. In a continued attempt to understand the differences between the brains of mentally healthy patients and those with schizophrenia, future studies by the research team at Penn will focus on identifying differences in interactive dynamics of proteins in the PSD.
The postmortem brain stimulation method, established in this study, breaks out of the boundaries of previous research using postmortem brain tissue. Postmortem studies have historically focused on snapshot analyses of the brain at the time of death. This new method allows investigation of functional responses of brain tissue to stimulation. "Our hope is that this study will shift our postmortem methodologies from limited comparative studies to a more experimental approach," explains Arnold. "This will allow us to tease apart the molecular complexities that contribute to mental illnesses such as schizophrenia."
- The researchers report their findings in this week's advanced online issue of Nature Medicine.