COMT and Developmental Memory Capacity

描述（由申请人提供）：记忆缺陷是与自闭症、智力低下和精神分裂症相关的致残障碍之一。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，从而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非青春期前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 活性升高会损害 2 个月大的小鼠的工作记忆，但不会损害 1 个月大的小鼠，其中 1 个月大的小鼠对应青春期。虽然人类和小鼠的这种相关性表明存在一个发育时间表，COMT 水平开始对工作记忆产生影响，但这些研究并没有提高特定大脑位点和发育时间点的 COMT 水平。高 COMT 活性影响工作记忆容量的精确解剖和细胞基质及其发育编程仍然知之甚少。该项目的目的是测试一个总体假设，即工作记忆和相关的突触可塑性在出生后发育过程中越来越依赖于内侧前额叶皮层或海马体的内源性多巴胺张力。为了验证这一假设，PI 开发了一种慢病毒载体，可以在时间和空间上上调小鼠大脑中的 COMT。一组研究人员将实现以下具体目标： 具体目标 1：确定内侧前额皮质或海马 COMT 表达升高对特定发育时间点工作记忆能力的影响。具体目标 2：确定内源性多巴胺张力在空间和时间上有针对性的减少对前额皮质和海马突触可塑性的影响。 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音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。识别内源性多巴胺音调诱导行为和细胞工作记忆表型所需的发育时间窗口、解剖区域和细胞基质将对我们对工作记忆的理解产生重大影响。由于在精神发育迟滞、自闭症和精神分裂症患者中观察到工作记忆缺陷，这一提议可能有助于更好地理解发育性神经精神疾病的一个方面的神经生物学基础。

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.