Mechanisms of Oestrogenic Modulation of Neural Circuitry

在英国，据估计，每四个成年人中就有一个在任何一年中经历过心理健康问题，每六个成年人中就有一个在任何给定的时间经历过心理健康问题（国家统计局精神病学报告，2001年）。其中一个例子就是精神分裂症患者。仅在英国，就有超过25万人被诊断患有精神分裂症，估计治疗这些患者的费用为67亿英镑。虽然精神分裂症很普遍，但对患者的治疗往往无效或无法治疗疾病的所有方面。已经提出了多个假设，涉及精神分裂症的一些脑系统及其功能障碍。这些理论的一些例子包括异常的脑化学和脑细胞（也称为神经元）之间的连接减少。多项研究表明，神经元之间的连接，称为突触，在精神分裂症患者的大脑中减少。这可能部分是由大脑发育过程中形成突触的分子的遗传修饰引起的。事实上，已经有人提出，通过开发控制神经元形状或控制大脑连接数量的药物，神经元可以相互重新连接，为精神分裂症提供一种新颖有效的治疗方法。目前，还没有开发出专门增加神经元之间连接数量的有效治疗方法。这部分是由于我们对大脑中的布线是如何实现的理解不足。因此，了解此类潜在药物是否以及如何允许神经元相互重新连接至关重要，以便为这种普遍性疾病提供新的、更有效的治疗方法。一段时间以来，人们都知道雌激素对大脑功能有积极的影响。最近，也有人提出，这些雌激素与抗精神病药物联合使用，可以改善男性和女性精神分裂症的治疗。但是雌激素如何对精神分裂症有益还不清楚。此外，长期使用雌激素治疗与心脏病甚至癌症的风险增加有关。避免这种不良副作用的一种方法是了解雌激素如何对精神分裂症患者有益，这将有助于开发更有效和更具体的药物。我们以前的研究已经证明，雌激素控制神经元之间突触的数量，从而控制它们之间传递的信息量。我们相信这个过程是雌激素对精神分裂症有益的一部分。我们的研究使用培养皿中生长的神经元，这种技术为研究雌激素在控制突触中的作用提供了一个起点，并使我们能够就它们在患病细胞模型中的作用提出具体问题。在本提案中，我们将确定雌激素是否可以影响神经元的形成方式，以及它们如何增加神经元上突触的数量。我们将使用复杂和尖端的细胞成像技术来问这些问题。令人兴奋的是，这些研究将使我们了解雌激素在控制神经元与突变蛋白之间的连接数量方面的有效性，这些突变蛋白被认为对精神分裂症等疾病很重要。这些实验的结果将提供关于潜在的雌激素为基础的治疗如何控制神经元在精神分裂症细胞模型中相互连接的方式的重要信息。回答这些问题对于我们开始开发潜在的新的治疗策略来治疗精神分裂症患者所经历的衰弱症状是至关重要的。

In the UK it is estimated that 1 in 4 adults experience mental health problems in any one year, and 1 in 6 experiences this at any given time (The Office for National Statistics Psychiatric Morbidity report, 2001). One example of this are people who with schizophrenia. In the UK alone, there are over 250,000 people diagnosed with schizophrenia, and this is estimated to cost £6.7 billion to treat these patients. Although schizophrenia is widespread, therapies for patients are often ineffective or fail to treat all aspects of the disorder. Multiple hypotheses have been proposed that implicate a number of brain systems and their dysfunction in schizophrenia. Some examples of these theories include abnormal brain chemistry and reduced connections between brain cells, also known as neurons. Multiple studies suggest that connections between neurons, called synapses, are reduced in the brains of suffers of schizophrenia. This may be in part caused by genetic modifications in molecules that shape synapses during brain development. Indeed, it has been proposed that by developing drugs that control how neurons are shaped or control the number of connections in the brain, neurons can re-connect with each other, offering a novel and effective treatment for schizophrenia. Currently, no effective treatment has been developed that specifically increase the number of connections between neurons. This is due in part to our poor understanding of how wiring in the brain is achieved. Therefore, it is vital to understand whether, and how, such potential agents can allow neurons to re-connect with each other, such that new and more effective treatments can be generated for this pervasive disorder. It has been known for some time that oestrogens can have a positive effect on brain function. More recently, it has also been suggested that these oestrogens, in combination with antipsychotic medications, can improve treatment of schizophrenia in men and women. But how oestrogens are beneficial in schizophrenia is not known. Moreover, long-term treatment with oestrogens is associated with increased risk of developing heart conditions and even cancer. One way to avoid such adverse side-effects is to understand how oestrogens are beneficial for schizophrenic patients, which would allow for the development of more effective and specific drugs. Our previous studies have demonstrated that oestrogens control the number of synapses between neurons, and thus control the amount of information that passes between them. We believe that this process is part of how oestrogens can be beneficial in schizophrenia. Our research uses neurons grown in dishes, a technique which provides a starting point to investigating the role of oestrogens in controlling synapses, and allows us to ask specific questions about their role in models of diseased cells. In this proposal, we will determine whether oestrogens can shape how neurons are formed, and how they can increase the number of synapses on neurons. We will use sophisticated and cutting-edge cellular imaging technique to ask these questions. Excitingly, these studies will allow us to understand how effective oestrogens are in controlling the number of connections between neurons with mutant proteins that are considered to be important for disorders such as schizophrenia. The results of these experiments will provide important information about how potential oestrogen-based therapies can control the way that neurons connect with each other in cellular models of schizophrenia. Answering these questions is essential for us to start to developing potential new therapeutic strategy in treating the debilitating symptoms that schizophrenic patients experience.