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

心理健康状况是我们面临的最具挑战性的医疗问题之一。社会的成本和家庭的负担都非常高。据估计，仅在2004/5年度，英国的费用就高达67亿英镑。精神分裂症的成本对个人和他们的家庭来说是非常高的，大约50%的精神分裂症患者企图自杀。最近的基因研究揭示了一些在产生精神健康状况中起作用的候选分子。在大脑的突触中发现了大量的这些分子。突触是允许脑细胞（或神经元）相互交流的结构。其中一种出现在突触上的分子被称为精神分裂症1号紊乱分子（DISC1），是由爱丁堡的Kirsty Millar和David Porteus及其同事发现的。这种基因发生突变会增加患精神疾病的几率，包括精神分裂症、双相情感障碍、复发性重度抑郁症和自闭症。我们最近发现DISC1影响突触可塑性。突触的可塑性是指突触改变其传输特性的能力，从而改变细胞之间交流的“响度”或增益。突触可塑性被认为与记忆有关。突触可塑性的丧失可以解释在这些衰弱的条件下看到的工作记忆（以及一般的认知功能）的缺陷。我们发现，DISC1需要在出生后一周左右的短时间内正常工作，以防止成年后大脑皮层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确定当DISC1出现故障并导致成人突触可塑性丧失时，皮层发育究竟出了什么问题。我们将首先在大脑皮层的一个简单部分——桶状皮层中研究这一过程，因为它的组织结构相对简单，而且我们对它了解很多。然后，我们可以看看类似的发育问题是否发生在大脑皮层的其他部分，比如前额叶皮层，这被认为是精神分裂症患者的主要问题。了解皮层中神经元之间的连接是如何被DISC1破坏的，将有助于我们制定治疗这些疾病的补救措施。

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.