The role of DISC1 in synaptic function and circuit formation during critical periods of cortical development

心理健康问题是我们面临的最具挑战性的医学问题之一。给社会带来的代价和家庭的负担都是非常高的。据估计，仅在英国，2004/5年度的费用就高达67亿英镑。仅精神分裂症对个人及其家人来说就非常昂贵，约50%的精神分裂症患者试图自杀。最近的遗传学研究揭示了一些候选分子，它们在产生心理健康状况方面发挥了作用。在大脑的突触中发现了大量这样的分子。突触是允许脑细胞(或神经元)相互交流的结构。在突触处存在的一种这样的分子被称为精神分裂症1，或DISC1，由爱丁堡的克斯蒂·米勒和大卫·波特乌斯及其同事发现。该基因的突变会增加患精神分裂症、双相情感障碍、反复发作的抑郁症和自闭症等多种精神疾病之一的几率。我们最近发现DISC1影响突触的可塑性。突触可塑性是指突触能够改变它们的传输特性，从而改变细胞之间相互交流的“响度”或增益。突触的可塑性被认为与记忆有关。突触可塑性的丧失可能是在这些衰弱条件下工作记忆(和一般认知功能)出现缺陷的原因。我们发现，DISC1需要在出生后短短一周左右的时间内正常工作，以防止成年后大脑皮质部分突触可塑性的丧失。在目前的研究中，我们建议尽可能密切地识别当DISC1故障并导致成人突触可塑性丧失时，皮质发育中到底出了什么问题。我们最初将在大脑皮层的一个简单部分来研究这一过程，这一部分被称为桶皮质，因为它的组织相对简单，而且人们对它有很多了解。然后，我们可以观察大脑皮质的其他部分是否也出现了类似的发育问题，比如被认为在精神分裂症患者中问题尤其严重的前额叶皮质。了解DISC1是如何破坏大脑皮层神经元之间的连接的，将有助于我们制定治疗这些疾病的药物。

Mental Health conditions are among the most challenging medical problems we face. The cost to society and the burden on families of are extremely high. Costs were estimated to be £6.7 billion pounds in England alone in 2004/5. The cost of schizophrenia alone is very high to the individuals and their families and some 50% of schizophrenics attempt suicide. Recent genetic studies have revealed a number of candidate molecules that play a role in producing mental health conditions. A large number of these molecules are found in synapses in the brain. Synapses are the structures that allow brain cells (or neurones) to communicate with one another. One such molecule present at the synapse is known as Disrupted in Schizophrenia 1, or DISC1, and was discovered by Kirsty Millar and David Porteus and colleagues in Edinburgh. Having a mutation in this gene can increase the chances of suffering from one of a number of mental disorders including schizophrenia, bipolar disorder, recurrent major depression and autism. We have recently discovered that DISC1 affects synaptic plasticity. Synaptic plasticity is the ability of synapses to change their transmission properties and hence alter the "loudness" or gain with which cells communicate with one another. Synaptic plasticity is thought to be responsible for memory. A loss of synaptic plasticity could account for the deficits in working memory (and cognitive function in general) seen in these debilitating conditions. We found that DISC1 needs to be working properly during a short period of a week or so following birth to prevent the loss of synaptic plasticity in part of the brain known as the cerebral cortex in adulthood. In the present study, we propose to identify as closely as we can what exactly goes wrong in development of the cortex when DISC1 malfunctions and results in a loss of synaptic plasticity in the adult. We will initially study this process in a simple part of the cortex known as the barrel cortex, because its organisation is relatively straightforward and a lot is known about it. We can then look to see if similar developmental problems occur in other parts of the cortex, like the prefrontal cortex, which is thought to be particularly problematic in schizophrenics. Understanding how the connections made between neurones in the cortex are disrupted by DISC1 will help us to formulate remedies to treat these conditions.