DEVELOPMENTAL PSYCHOPATHOLOGY

该中心提出了四个假设，以确定遗传多态性在精神分裂症中的作用，模仿科赫的经典感染假设：（1）鉴定与疾病相关的基因中的多态性，（2）证明多态性对基因功能或表达的功能影响，（3）多态性与脑功能缺陷的关系，和（4）通过针对脑功能缺陷的治疗逆转脑功能缺陷。 细胞功能障碍大多数基因神经递质受体在大脑的发育中起着重要的作用。这个项目的重点是假设3的一个特定部分，特别是遗传多态性与大脑功能发育缺陷的关系。伦纳德博士（项目0001）已经确定了CHRNA 7启动子中的多态性，这些多态性降低了基因表达，并与成人中的（a）听觉抑制生理学效应相关， 测量（P50感觉门控）和（B）精神分裂症风险增加。编码儿茶酚-O-甲基-转移酶的基因是与精神分裂症相关症状和神经心理缺陷相关的第二个基因。关键是要检查功能多态性和生理， 神经认知和症状性缺陷可以扩展到早期发育阶段，包括婴儿、儿童和青少年。该项目将评估，在婴儿中，CHRNA 7多态性和抑制缺陷之间的关系，利用脑电图。（具体目标1）。将在儿童和青少年中检查CHRNA 7和COMT的遗传多态性与神经认知缺陷（特定目标#2）和症状性非精神病性疾病（例如ADHD;特定目标#3）之间的关系。本项目将与分子表型的发育研究（项目0001）和药物开发（项目0004）协调，以探索功能遗传多态性在发育精神病理学中的作用。希望阐明CHRNA 7的发育作用将为精神分裂症一级预防中的翻译工作提供信息。

The Center proposes four postulates for establishing the role of a genetic polymorphism in schizophrenia, modeled on Koch's classical postulates for infection: (1) identification of a polymorphism in a gene linked with illness, (2) demonstration of a functional effect of the polymorphism on gene function or expression, (3) relation of the polymorphism to deficits in brain function, and (4) reversal of the deficits in brain function by treatment directed at the cellular dysfunction. Most genes neurotransmitter receptors have substantial roles in the development of the brain. This project focuses on a specific portion of postulate 3, specifically the relationship of a genetic polymorphism to developmental deficits in brain function. Dr Leonard (Project 0001) has identified polymorphisms in the CHRNA7 promotor that decrease gene expression and are associated, in adults, with (a) an auditory inhibitory physiological measure (P50 sensory gating) and (b) an increased risk for schizophrenia. The gene which codes for CatechoI-O-MethyI-Transferase is a second gene associated with schizophrenia-related symptoms and neuropsychological deficits. It is critical to examine whether these associations between functional polymorphisms and physiological, neurocognitive, and symptomatic deficits can be extended to earlier periods of development, including infants, children, and young adolescents. This Project will assess, in infants, the relationship between CHRNA7 polymorphisms and inhibitory deficits utilizing EEG. (Specific Aim # 1). The relationship between genetic polymorphisms in CHRNA7 and COMT and neurocognitive deficits (Specific Aim #2) and symptomatic non-psychotic illness (e.g. ADHD; Specific Aim #3) will be examined in children and adolescents. This Project will coordinate with developmental studies of molecular phenotyping (Project 0001), and drug development (Project 0004) to explore the role of functional genetic polymorphisms in Developmental Psychopathology. It is hoped that clarifying the developmental role of CHRNA7 will inform translational efforts in the primary prevention of schizophrenia.