Molecular Mechanisms of ADHD in Neurofibromatosis Type 1

项目摘要/摘要 1型神经纤维瘤病(NF1)是一种常见的遗传性疾病，具有各种症状，大多数 常见为神经皮损和发育障碍，较少见的是肿瘤。认知 注意力缺陷等症状影响高达80%的被诊断为注意力缺陷的患者 据估计，NF1患者中有50%的人患有多动症(ADHD)。与普通民众不同，人们的注意力 在NF1中，身体缺陷对男孩和女孩的影响是平等的。很少有研究对其潜在机制进行研究。 导致NF1儿童多动症的高发病率。使用NF1的小鼠实验模型系统， 小鼠NF1基因单倍体不足(NF1+/-)，我们在雄性小鼠中的初步数据显示，行为缺陷 抑制是ADHD的一个关键成分，表现为旷野中的多动，增加了悬崖跌倒的频率 回避反应任务，在延迟折扣任务中小奖励选择的频率增加，可挽救 注意缺陷多动障碍药物(鸟嘌呤0.3 mg/kg，i.p.)行政管理。这项拟议研究的第一个目标是 阐明行为抑制缺陷背后的大脑机制，并将有能力发现男性 和女性的行为差异和相应的回路活动测量，包括活体记录 在前额叶皮质。在第二个目标中，我们提出了对这些观察到的行为的遗传拯救 抑制缺陷。NF1是由神经纤维素水平降低引起的，神经纤维素是一种RAS GTP酶激活蛋白， 导致Ras-MAPK-ERK过度激活。目前，认知障碍还没有可用的治疗方法。 在NF1中，靶向RAS-MAPK-ERK过度激活。该项目提出了一种治疗糖尿病的新机制。 NF1通过调节泛素蛋白酶体恢复神经纤维蛋白水平引起的认知缺陷 路径。总体而言，该项目将表征潜在的行为抑制的临床相关回路 缺陷，这是ADHD的一个关键特征，在男性和女性中。此外，这项提案将解决对 NF1的治疗目标有可能解决患者可能经历的许多症状 包括认知障碍、肿瘤和神经皮肤症状。神经纤维蛋白泛素的调节- 蛋白酶体途径可能为NF1的治疗提供一个新的、更安全的药理靶点。

PROJECT SUMMARY/ABSTRACT Neurofibromatosis type 1 (NF1) is a common inherited genetic disorder with a variety of symptoms, most commonly as neurocutaneous lesions and developmental disorders, and less commonly with tumors. Cognitive symptoms such as attentional deficits affect up to 80% of patients, with diagnosis of attention deficit hyperactivity disorder (ADHD) estimated at 50% in NF1 patients. Unlike the general population, attention deficits affect boys and girls equally in NF1. Few studies have investigated the underlying mechanisms contributing to high incidence of ADHD diagnosis in NF1. Using a murine experimental model system of NF1, mice haploinsufficient for the NF1 gene (Nf1+/-), our preliminary data in male mice show deficits in behavioral inhibition, a key component of ADHD, as exhibited by hyperactivity in open field, increased fall frequency in cliff avoidance reaction task, and increased frequency of small reward choice in delay discounting task, rescuable by ADHD medication (guanfacine 0.3 mg/kg, i.p.) administration. The first aim of this proposed study will elucidate the brain mechanisms underlying deficits in behavioral inhibition, and will be powered to detect male and female differences in behavior and corresponding measures of circuitry activity including in vivo recordings in the prefrontal cortex. In the second aim, we propose a genetic rescue for these observed behavioral inhibition deficits. NF1 is caused by reduced levels of neurofibromin, a RAS GTPase-activating protein, resulting in RAS-MAPK-ERK hyperactivation. Currently, there are no available treatments for cognitive deficits in NF1 that target RAS-MAPK-ERK hyperactivation. This project, proposes a novel mechanism for treatment of cognitive deficits in NF1 by restoring neurofibromin levels through modulation of the ubiquitin-proteasome pathway. Overall, this project will characterize clinically relevant circuits underlying behavioral inhibition deficits, a key feature of ADHD, in males and females. Additionally, this proposal will address the need for a treatment target in NF1 that has the potential to address the many symptoms patients may experience including cognitive deficits, tumors, and neurocutaneous symptoms. Modulation of the neurofibromin ubiquitin- proteasome pathway may provide a novel and safer pharmacologic target for treating NF1.