Molecular Mechanisms of ADHD in Neurofibromatosis Type 1

项目总结/摘要 1型神经纤维瘤病（NF 1）是一种常见的遗传性疾病，具有多种症状， 常见于神经皮肤病变和发育障碍，较少见于肿瘤。认知 注意力缺陷等症状影响高达80%的患者，诊断为注意力缺陷 多动障碍（ADHD）在NF 1患者中估计为50%。与一般人群不同，注意力 在NF 1中，缺陷对男孩和女孩的影响是一样的。很少有研究调查了潜在的机制 导致NF 1中ADHD诊断的高发生率。使用NF 1的小鼠实验模型系统， NF 1基因单倍型不足的小鼠（Nf 1 +/-），我们在雄性小鼠中的初步数据显示， 抑制，ADHD的一个关键组成部分，表现为在开放领域的多动，增加了悬崖下降的频率 回避反应任务，以及延迟折扣任务中小奖励选择的频率增加，可挽救 通过ADHD药物（胍法辛0.3mg/kg，i. p.）局这项研究的第一个目的是 阐明行为抑制缺陷背后的大脑机制，并将有能力检测男性 行为和相应的电路活动测量（包括体内记录）的女性差异 大脑前额叶皮层在第二个目标中，我们提出了一个遗传拯救这些观察到的行为， 抑制缺陷NF 1是由神经纤维蛋白（一种RAS GTP酶激活蛋白）水平降低引起的， 导致RAS-MAPK-ERK过度活化。目前，对于认知缺陷， 在NF 1中靶向RAS-MAPK-ERK过度活化。该项目提出了一种新的治疗机制， 通过调节泛素-蛋白酶体恢复神经纤维蛋白水平导致NF 1认知缺陷 通路总的来说，这个项目将表征行为抑制的临床相关电路 缺陷，多动症的一个关键特征，在男性和女性。此外，该提案还将满足以下需要： NF 1的治疗目标，有可能解决患者可能遇到的许多症状 包括认知缺陷、肿瘤和神经皮肤症状。调节神经纤维蛋白泛素- 蛋白酶体途径可能为治疗NF 1提供新的、更安全的药理学靶点。

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.