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Prefrontal cortical dysfunction in Rett syndrome

雷特综合征的前额皮质功能障碍

基本信息

批准号：
9229746
负责人：
David M. Katz
金额：
$ 39.63万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9229746
关键词：
Affect Amygdaloid structure Animals Anterior Apnea Arousal Autistic Disorder Behavior Behavior Control Behavioral Biochemical Biological Models Birth Brain Brain Stem Breathing Cessation of life Cognitive Defect Dendritic Spines Development Electrophysiology (science)Enzymes Female Fostering Foundations Frequencies Functional disorder Generations Genes Growth Health Hyperventilation Immediate-Early Genes Impairment Infusion procedures Intervention Knockout Mice Label Light Link Medial Mediating Midbrain structure Modeling Motor Mus Mutant Strains Mice Mutation NMDA receptor A1 Neurodevelopmental Disorder Neurologic Neurologic Dysfunctions Neurons Output Pathway interactions Patients Phenotype Phosphorylation Physiological Play Prefrontal Cortex Presynaptic Terminals Prosencephalon Proteins Pseudorabies Quality of life Regulation Research Research Design Respiration Respiration Disorders Respiratory Signs and Symptoms Rest Rett Syndrome Ribosomal Protein S6 Role Signal Transduction Signaling Molecule Site Slice Source Staining method Stains Structure Structure of terminal stria nuclei of preoptic region Surrogate Markers Symptoms Synapses Testing Therapeutic Viral Viral Vector Western Blotting Work autism spectrum disorder base behavior influence chemical genetics clinically relevant density designer receptors exclusively activated by designer drugs effective therapy extracellular functional outcomes gene product genetic approach genetic technology hippocampal pyramidal neuron improved in vivo innovation loss of function mutation midbrain central gray substance mouse model mutant novel therapeutic intervention protein expression recombinase research study respiratory response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Rett syndrome (RTT) is a severe neurodevelopmental disorder on the autism spectrum that is caused by mutations in the MECP2 gene and affects approximately 1/10,000 female births worldwide. In addition to cognitive, motor and behavioral deficits, one of the most physically debilitating consequences of RTT is severe disruption in the control of breathing, and approximately 25% of RTT patients die prematurely of cardiorespiratory complications. Currently, there are no treatments available for breathing disorders or any other neurological deficit in RTT. To develop effective treatments, it is essentia that we understand how brain circuits that control breathing are disrupted by MECP2 mutations, so that therapeutic targets for restoring normal function can be identified. Therefore, the proposed research will use Mecp2 mutant mice, a well- defined model of RTT to define defects in brain circuit function that perturb normal breathing, including the role of deficits in ribosoma protein S6 (rpS6), a key signaling molecule whose activity is severely decreased in RTT mice. These studies focus in particular on the medial prefrontal cortex (mPFC), a region that we recently found is severely hypofunctional in Mecp2 mutant mice and which is critical for behavioral regulation of breathing, as well as cognitive and other brain functions. We will specifically examine the possibility that reversing circuit defects in the mPFC by interventions that either restore normal levels of neuronal activity or promote synaptic growth and function by increasing rpS6 signaling will reverse respiratory symptoms and other abnormalities in Mecp2 mutants. These studies will include electrophysiological recording in brain slices, physiological and behavioral analyses in intact animals and biochemical and morphological studies of synaptic structure and function, using state-of-the-art chemical-genetic technologies for manipulating the activity of neurons and activity of rpS6 in the mPFC. By defining mechanisms that underlie mPFC dysfunction in Mecp2 mutants, it is hoped these studies will foster development of new therapeutic strategies for breathing disorders and other impairments in RTT patients. Moreover, because mPFC dysfunction is also implicated in non- syndromic autism, our findings may be more broadly applicable to patients on the autism spectrum as a whole.

描述（由申请人提供）：Rett综合征（RTT）是自闭症谱系中的一种严重神经发育障碍，由MECP 2基因突变引起，影响全球约1/10，000的女性新生儿。除了认知、运动和行为缺陷之外，RTT最使身体衰弱的后果之一是呼吸控制的严重中断，并且大约25%的RTT患者过早死于心肺并发症。目前，RTT中没有呼吸障碍或任何其他神经功能缺损的治疗方法。为了开发有效的治疗方法，我们必须了解控制呼吸的大脑回路是如何被MECP 2突变破坏的，以便确定恢复正常功能的治疗目标。因此，拟议的研究将使用Mecp 2突变小鼠，一种定义明确的RTT模型来定义干扰正常呼吸的脑回路功能缺陷，包括核糖体蛋白S6（rpS 6）缺陷的作用，这是一种关键的信号分子，其活性在RTT小鼠中严重降低。这些研究特别关注内侧前额叶皮层（mPFC），我们最近发现Mecp 2突变小鼠的这一区域功能严重低下，这对呼吸行为调节以及认知和其他大脑功能至关重要。我们将专门研究的可能性，扭转电路缺陷的mPFC的干预，无论是恢复正常水平的神经元活动或促进突触的生长和功能，通过增加rpS 6信号将扭转呼吸道症状和其他异常的Mecp 2突变体。这些研究将包括脑切片的电生理记录，完整动物的生理和行为分析，以及突触结构和功能的生物化学和形态学研究，使用最先进的化学遗传技术来操纵mPFC中神经元的活性和rpS 6的活性。通过定义Mecp 2突变体中mPFC功能障碍的机制，希望这些研究将促进RTT患者呼吸障碍和其他损伤的新治疗策略的开发。此外，由于mPFC功能障碍也与非综合征型自闭症有关，因此我们的研究结果可能更广泛地适用于整个自闭症谱系的患者。