COMT and Developmental Memory Capacity

描述（由申请人提供）：记忆缺陷是与自闭症、精神发育迟滞和精神分裂症相关的致残性损伤之一。由于记忆障碍的潜在遗传和神经机制仍然知之甚少，因此不存在基于机制的治疗方案来改善这种障碍，阻碍了患者有效融入社会。有趣的是，儿茶酚-O-甲基转移酶（COMT）的高活性等位基因与儿童和青少年青春期后而不是青春期前的较低水平的工作记忆表现相关。我们发表的小鼠研究表明，人类COMT的活性升高会损害2个月龄但不影响1个月龄小鼠的工作记忆，其中1个月龄对应于小鼠的青春期。虽然人类和小鼠中的这种相关性表明存在COMT水平开始对工作记忆产生影响的发育时间表，但这些研究并没有在特定的大脑位点和发育时间点提高COMT水平。精确的解剖和细胞底物及其发育编程，通过高COMT活性影响工作记忆容量仍然知之甚少。拟议的项目的目的是测试的总体假设，工作记忆和相关的突触可塑性变得越来越依赖于内源性多巴胺在内侧前额叶皮层或海马在出生后的发展。为了验证这一假设，PI已经开发了一种慢病毒载体，其在时间和空间上上调小鼠脑中的COMT。一组研究人员将实现以下具体目标：具体目标1：确定在特定发育时间点，内侧前额叶皮层或海马中COMT表达升高对工作记忆能力的影响。具体目标二：确定内源性多巴胺张力在空间和时间上的靶向降低对前额叶皮层和海马突触可塑性的影响。 在完成拟议的研究后，这些技术创新的实验将首次确定内源性多巴胺张力决定工作记忆能力和突触可塑性发育成熟的解剖学和细胞机制。确定内源性多巴胺张力诱导行为和细胞工作记忆表型所需的发育时间窗、解剖区域和细胞基质将对我们理解工作记忆产生重大影响。由于工作记忆缺陷已被观察到在个人与精神发育迟滞，自闭症和精神分裂症，这一建议可能会导致更好地了解神经生物学基板的一个方面的发育性神经精神障碍。

DESCRIPTION (provided by applicant): Memory deficits are one of the disabling impairments associated with autism, mental retardation, and schizophrenia. Because the underlying genetic and neuronal mechanisms of memory impairments are still poorly understood, mechanism-based therapeutic options do not exist to ameliorate such impairment, hindering the effective integration of patients into society. Interestingly, a high activity allele of catechol-O-methyl-transferase (COMT) is associated with lower levels of working memory performance after, but not before, puberty in children and adolescents. Our published mouse work shows that elevated activity of human COMT impairs working memory of mice at 2 months but not 1 month of age, where 1 month of age corresponds to puberty in the mouse. While this correlation in humans and mice suggests that there is a developmental timetable along which COMT levels begin to exert an influence on working memory, these studies did not elevate COMT levels at specific brain loci and developmental time points. The precise anatomical and cellular substrates and their developmental programming through which high COMT activity affects working memory capacity are still poorly understood. The objective of the proposed project is to test the overarching hypothesis that working memory and associated synaptic plasticity become increasingly dependent on an endogenous dopamine tone in the medial prefrontal cortex or hippocampus during postnatal development. To test this hypothesis, the PI has developed a lentiviral vector that temporally and spatially up-regulates COMT in the mouse brain. A team of investigators will achieve the following Specific Aims: Specific Aim 1: To ascertain the impact of elevated COMT expression in the medial prefrontal cortex or hippocampus on working memory capacity at specific developmental time points. Specific Aim 2: To determine the impact of spatially and temporally targeted reductions in an endogenous dopamine tone on synaptic plasticity in the prefrontal cortex and hippocampus. Upon completion of the proposed studies, these technically innovative experiments will, for the first time, identify the anatomical and cellular mechanisms through which an endogenous dopamine tone determines the developmental maturation of working memory capacity and synaptic plasticity. Identifying the developmental time window, anatomical region(s), and cellular substrate(s) necessary for an endogenous dopamine tone to induce behavioral and cellular working memory phenotypes will have a major impact on our understanding of working memory. Because working memory deficits have been observed in individuals with mental retardation, autism, and schizophrenia, this proposal could lead to a better understanding of the neurobiological substrates for one aspect of developmental neuropsychiatric disorders.