Memory Mechanisms and Mental Disorders

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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.