近日,，美國賓西法尼亞大學(xué)醫(yī)學(xué)院研究人員發(fā)現(xiàn)在精神分裂癥死者大腦組織中二乙基溴乙酰胺受體活性顯著失調(diào),。研究人員通過刺激額前皮質(zhì)中的受體增加了erbB4受體活性水平，與精神分裂癥患者組織中的NMDA受體活性降低一樣,。研究顯示存在一種降低NMDA受體功能的機(jī)制,，并且這種機(jī)制在精神分裂癥中可能長期存在,，研究結(jié)果公布在本周的《自然醫(yī)學(xué)》（Nature medicine）網(wǎng)絡(luò)版中,。

        精神分裂癥是一種精神錯(cuò)亂,，全球發(fā)病率大概是1％，其主要特征癥狀有：幻覺,、妄想癥和行為紊亂等。先前對精神分裂癥患者大腦的研究顯示其改變了額前皮質(zhì)的功能,、大腦的認(rèn)知功能組織中心,、個(gè)性表達(dá)和行為控制。

        目前,，全球大規(guī)模的精神分裂癥遺傳研究聚焦在一種神經(jīng)調(diào)節(jié)蛋白——NRG1中,，該蛋白似乎在決定一個(gè)人是否易患某種疾病上具有重要的作用。

        研究人員使用NRG1蛋白激活二乙基溴乙酰胺受體erbB4以測試死者大腦組織中的分子反應(yīng),。他們通過將磷酸分子加入受體將NRG1綁定到erbB4,，進(jìn)而刺激二乙基溴乙酰胺受體活性，erbB4活性便依次切斷神經(jīng)元中的級聯(lián)分子事件,。在初步比較心理健康和精神分裂癥患者死者大腦組織中的神經(jīng)化學(xué)物質(zhì)活性之后,，研究人員發(fā)現(xiàn)NRG1-erbB4活性在精神分裂癥患者大腦中有極大的提高。

        這種次級神經(jīng)元受體叫做NMDA,，能接收神經(jīng)遞質(zhì)傳遞的信號,。先前的研究表明erbB4和NMDA受體活性使得研究人員認(rèn)為增強(qiáng)erbB4受體活性會(huì)導(dǎo)致NMDA受體活性降低。

        低水平的NMDA受體活性被認(rèn)為是導(dǎo)致精神分裂癥癥狀的原因,。通過用谷氨酸刺激NMDA受體,，隨后測量受體中磷酸化的改變,，研究人員能在精神分裂癥患者尸體大腦組織中追蹤NMDA受體活性。

        研究人員推測精神分裂癥可能部分是由突簇后密度蛋白（PSD）中多種因子（遺傳和后天）共同影響導(dǎo)致,，在細(xì)胞環(huán)境中的分子之間相互作用最終導(dǎo)致精神分裂癥癥狀產(chǎn)生,。接下來的研究將集中于PSD蛋白中分子相互作用的差異上.

多巴胺過敏與精神分裂癥

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D-Ser－NMDA受體的一種新的調(diào)控因子

NMDA受體在學(xué)習(xí)和記憶中的中心作用

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.