Dopaminergic regulation by D-aminoacid oxidase, an enzyme implicated in schizophrenia

谷氨酸和多巴胺是大脑的化学物质(神经递质？)大多数人与严重的精神疾病有关，这种疾病被称为精神分裂症。大脑中调节谷氨酸信号的分子之一是D-氨基酸氧化酶(DAO)。它通过分解另一种分子D-丝氨酸来做到这一点，D-丝氨酸是谷氨酸信号正常工作所必需的。我们实验室和其他实验室最近的发现表明，DAO和D-丝氨酸在精神分裂症中受到影响。尤其是在疾病患者的大脑中，DAO太多，太活跃。这导致了一种理论，即DAO过多而D-丝氨酸不足可能是谷氨酸问题的一部分。在精神分裂症中，并可能导致一些关键症状和困难的患者所经历的疾病。这个项目将研究一个特定的问题，即DAO在大脑中起什么作用，以及为什么它与精神分裂症有关。如上所述，多巴胺和谷氨酸都与精神分裂症有关，但我们对这两种神经递质之间的关系知之甚少。我们最近发现，DAO出人意料地存在于大脑中制造多巴胺的区域，这表明DAO可能提供了其中一个联系。因此，我们想利用一种新的药物来研究降低DAO活性对大脑中多巴胺功能的影响。我们还将准确地映射DAO与多巴胺神经细胞的关系，以帮助解释它是如何发挥作用的。这个项目建立在我们最近的发现和现有的专业知识基础上，考虑到DAO对精神分裂症的病因和治疗的兴趣，这个项目是及时和重要的。

Glutamate and dopamine are the brain chemicals (?neurotransmitters?) most involved in the severe mental illness called schizophrenia. One of the molecules that regulates glutamate signalling in the brain is D-amino acid oxidase (DAO). It does this by breaking down another molecule, D-serine, that is needed for glutamate signalling to work properly. Recent findings from our lab and others show that DAO and D-serine are affected in schizophrenia. In particular, there is too much DAO, and it is too active, in the brains of people with the illness. This leads to the theory that excessive DAO, and not enough D-serine, may be part of the ?glutamate problem? in schizophrenia and may contribute to some of the key symptoms and difficulties which patients with the illness experience. This project will examine a specific question about what DAO does in the brain and why it is relevant to schizophrenia. As noted above, dopamine as well as glutamate is involved in schizophrenia, yet we know little of the relationship between the two neurotransmitters. We recently found that DAO is, unexpectedly, present in the area of the brain that makes dopamine, suggesting that DAO may provide one of the links. We therefore want to study the effect of decreasing DAO activity on the function of dopamine in the brain, using a novel drug available to us. We will also map exactly where DAO is in relation to the dopamine nerve cells to help explain how and where it works. This project build upon our recent findings and current expertise, and is timely and important given the interest in DAO in the cause and the treatment of schizophrenia.