Deep brain stimulation in Rett syndrome mice: cognitive benefits and their mechanisms

项目摘要/摘要 在过去的十年中，深部脑刺激(DBS)治疗运动疾病的成功，如 帕金森氏症和肌张力障碍有两个方面的扩展：它现在被用来治疗神经精神疾病 成年人的疾病，如强迫症和阿尔茨海默病(AD)，而且正在开始 应用于儿童运动和神经精神疾病的治疗(肌张力障碍和抽动症， )。例如，一项初步研究表明，穹隆刺激可以改善AD患者的症状 海马体依赖的记忆任务并减缓认知衰退，而在啮齿动物中，刺激海马伞- 穹隆(FFX)或内嗅皮质改善空间记忆，可能是通过调节海马theta-Gamma来实现的 颤动，成人神经发生，或两者兼而有之。我们最近发现穹隆DBS增强了海马区 小鼠学习记忆与海马区突触可塑性和齿状神经发生的关系 雷特综合征(RTT)是女性智力残疾的主要原因。主要由突变引起 这损害了MeCP2的功能，MeCP2是一种表观遗传转录调节因子，其确切活性是 深入调查的对象，RTT在女性出生第一年后表现出来，造成深刻的影响 认知障碍和一系列附加功能。受影响的儿童在出生时看起来很健康， 达到早期发育里程碑，但在12到18个月之间突然失去获得性运动， 语言和社交技能，并发展一系列神经和精神特征(手的刻板印象， 焦虑，自闭症行为，癫痫，自主神经功能障碍，以及运动障碍，包括肌张力障碍，痉挛， 和最终的帕金森症)。几种小鼠模型，要么完全缺乏MeCP2，要么携带 功能低下的等位基因，再现了疾病的广泛表型，从早期明显的健康到退化 运动功能障碍、社会和认知障碍的发生；海马体依赖学习和 记忆和海马突触可塑性受损。我们已经表明，星展银行拯救了这些 海马区的功能，但作用机制尚不清楚：我们假设有多种机制 (例如，海马神经发生、局部场电位振荡、海马体体积和/或全局神经 网络活动)可能正在工作。在本提案中，我们将(1)确定DBS影响的程度、持续时间 关于记忆益处、治疗的最佳频率和对老年动物的影响；(2)调查 可能的机制有助于RTT小鼠的益处；以及(3)确定记忆是否 穹隆DBS的益处可推广到其他智力残疾障碍的小鼠模型。数据 将提供对电路级别操作的价值的洞察，并有望导致 RTT和其他导致智力残疾的儿童障碍的新治疗方法。

PROJECT SUMMARY/ABSTRACT Over the past decade, the success of deep brain stimulation (DBS) to treat motor diseases such as Parkinson's and dystonia has been extended in two directions: it is now being used to treat neuropsychiatric diseases in adults, such as obsessive-compulsive disorder, and Alzheimer's disease (AD), and it is beginning to be applied in children to treat both motor and neuropsychiatric diseases (dystonia and Tourette's, respectively). For example, a pilot study showed that forniceal stimulation in AD patients improves hippocampus-dependent memory tasks and slows cognitive decline, and in rodents, stimulation of the fimbria- fornix (FFx) or entorhinal cortex improves spatial memory, likely by modulating hippocampal theta-gamma oscillation, adult neurogenesis, or both. We have recently shown that forniceal DBS enhances hippocampal learning and memory as well as hippocampal synaptic plasticity and dentate neurogenesis in a mouse model of Rett Syndrome (RTT), the leading cause of intellectual disability in females. Caused mainly by mutations that impair the function of MeCP2, an epigenetic transcriptional modulator whose precise activities are the subject of intensive investigation, RTT manifests in females after the first year of life, causing profound cognitive impairment and a wide range of additional features. Affected children appear healthy at birth and achieve early developmental milestones, but between 12 and 18 months suddenly lose acquired motor, language, and social skills and develop an array of neurological and psychiatric features (hand stereotypies, anxiety, autistic behaviors, seizures, autonomic dysfunction, and motor deficits including dystonia, spasticity, and eventual parkinsonism). Several mouse models, either completely lacking MeCP2 or carrying hypofunctional alleles, reproduce the broad phenotype of the disorder, from early apparent health to regression and development of motor dysfunction, social and cognitive deficits; hippocampus-dependent learning and memory and hippocampal synaptic plasticity are impaired. We have shown that DBS rescues these hippocampal features, but the mechanism of action remains unclear: we hypothesize that multiple mechanisms (e.g., hippocampal neurogenesis, local field potential oscillations, hippocampal volume, and/or global neural network activity) might be at work. In this proposal we will (1) determine the extent of DBS effects, the duration of memory benefits, the optimal frequency of treatment, and effects in older animals; (2) investigate the possible mechanisms that contribute to the benefits in RTT mice; and (3) determine whether the memory benefits of forniceal DBS are generalizable to other mouse models of intellectual disability disorders. The data will provide insights into the value of manipulations at the circuit level and will hopefully lead to the design of new therapeutic approaches to RTT and other childhood disorders causing intellectual disability.