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，基于机制的治疗方案不存在改善这种障碍的选择，阻碍了患者有效地融入社会。有趣的是，儿茶酚氧甲基转移酶(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之前的工作记忆表现水平较低有关。我们发表的小鼠研究表明，人类COMT活性增加会损害2个月龄小鼠的工作记忆，但不会损害1个月龄小鼠的工作记忆，1个月龄对应于小鼠的青春期。虽然在人类和老鼠身上的这种相关性表明，COMT水平开始影响工作记忆的发展时间表是存在的，但这些研究并没有提高特定大脑位置和发育时间点的COMT水平。高COMT活性影响工作记忆能力的精确解剖和细胞底物及其发育编程仍然知之甚少。这项提议的项目的目的是测试最重要的假设，即工作记忆和相关的突触可塑性在出生后的发育过程中越来越依赖于内侧前额叶皮质或海马区的内源性多巴胺音调。为了验证这一假设，PI开发了一种慢病毒载体，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：确定内侧前额叶皮质或海马区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：确定内源性多巴胺音调在空间和时间上的靶向性降低对前额叶皮质和海马区突触可塑性的影响。在拟议的研究完成后，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(S)和细胞底物(S)将对我们理解工作记忆产生重大影响。由于在智力低下、自闭症和精神分裂症的个体中观察到了工作记忆缺陷，这一建议可能有助于更好地理解发育性神经精神障碍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.