Memory Mechanisms and Mental Disorders

精神分裂症(SZ)和双相情感障碍(BP)是最慢性和最令人虚弱的精神综合征， 每种疾病的终生患病率约为1%。现有的药物治疗方法对 减轻症状严重程度，但不能改善潜在的疾病过程、认知缺陷或 与这些综合征相关的功能障碍。鉴于SZ和BP基本上都是 可遗传的基因发现代表着我们为干预寻找新的分子靶点的最大希望。 然而，这些综合征的高度多基因和异质性极大地降低了 传统遗传连锁和关联设计的有效性。此外，最近的证据表明 这些病症之间有一些基因重叠。我们的方法是基于这样一个前提，即SZ和 BP最好被概念化为一组数量性状，它们反映了 易感基因和症状表达(CEendophenotype 1)。在这里，我们将筛选30万个SNP 标记-分布以便能够在基因组的大多数部分检测到连锁不平衡- 记忆和社交能力表型与SZ和BP风险的关系 来自大洛杉矶地区的2000名受试者的样本(LA2K样本)。患者的随访研究 将进行SZ和BP检查，以确定LA2K样本中确定的基因对 SZ和BP病理生理的神经解剖和神经生理学指标。因为几乎 一半的基因组在大脑中表达，考虑到记忆和 社交适应行为的功能，很可能有几十到数百个基因的小到中等 在普通人群中影响这些表型的效果。 我们推测，这些基因中的许多通过对SZ和BP的影响而导致对SZ和BP的易感性 大脑系统调节记忆系统和社会功能，其中大多数是 未被以前的研究发现，使用症状状态作为表型目标。与这一整体并行 基因组策略，为了说明我们的翻译方法，我们将使用两个啮齿动物转基因模型 有希望的候选基因DISC1和dybindin来说明 这些基因与记忆力、社交能力以及对SZ和BP的易感性之间的关系。

Schizophrenia (SZ) and bipolar disorder (BP) are the most chronic and debilitating of psychiatric syndromes, each with lifetime prevalence of about 1%. Existing pharmacologic treatments are partially effective in reducing symptom severity but do not ameliorate the underlying disease processes, cognitive deficits, or functional disabilities associated with these syndromes. Given that both SZ and BP are substantially heritable, gene discovery represents our best hope for identifying new molecular targets for interventions. However, the highly polygenic and heterogeneous nature of these syndromes substantially reduces the effectiveness of traditional genetic linkage and association designs. In addition, recent evidence suggests that some genetic overlaps between these conditions. Our approach is based on the premise that SZ and BP are best conceptualized as sets of quantitative traits that reflect intermediate phenotypes between predisposing genes and syndromal expression (CEendophenotypes1). Here we will screen 300,000 SNP markers - distributed so as to enable the detection of linkage disequilibrium in most parts of the genome - for association with memory and sociability phenotypes previously associated with risk for SZ and BP in a sample of 2,000 subjects from the greater Los Angeles area (LA2K sample). Followup studies of patients with SZ and BP will be performed to specify the impact of the genes identified in the LA2K sample on neuroanatomical and neurophysiological indicators of the pathophysiology of SZ and BP. Because nearly half of the genome is expressed in the brain, and considering the central importance of memory and sociability to adaptive behavioral function, there are likely dozens to hundreds of genes of small to moderate effect influencing these phenotypes in the general population. We hypothesize that many of these genes contribute to susceptibility to SZ and BP through their impacts on the brain systems mediating memory systems and social function and that most of these have been undetected by previous studies using syndromal status as the phenotypic target. In parallel with this whole genome strategy, and to illustrate our translational approach, we will use rodent transgenic models of two promising candidate genes DISC1 and Dysbindin to specify the cellular mechanisms underlying the associations of these genes with memory, sociabiliy, and susceptibility to SZ and BP.