Prefrontal cortical dysfunction in Rett syndrome

雷特综合征的前额皮质功能障碍

• 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
• 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

 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）：雷特综合征 (RTT) 是一种严重的自闭症谱系神经发育障碍，由 MECP2 基因突变引起，影响全球约 1/10,000 的女性新生儿。 RTT 最严重的身体衰弱后果之一是呼吸控制的严重破坏，大约 25% 的 RTT 患者因心肺并发症过早死亡，目前尚无治疗方法。为了开发有效的治疗方法，我们必须了解 MECP2 突变如何扰乱控制呼吸的大脑回路，从而确定恢复正常功能的治疗靶点。拟议的研究将使用 Mecp2 突变小鼠（一种明确的 RTT 模型）来定义扰乱正常呼吸的脑回路功能缺陷，包括核糖体蛋白 S6 (rpS6) 缺陷的作用，核糖体蛋白 S6 是一种关键信号分子，其活性这些研究特别关注内侧前额叶皮层 (mPFC)，我们最近发现 Mecp2 突变小鼠的该区域功能严重减退，对于呼吸、认知和其他行为调节至关重要。我们将专门研究通过恢复神经元活动正常水平或通过增加 rpS6 信号传导促进突触生长和功能的干预措施来逆转 mPFC 中的回路缺陷，从而逆转呼吸道症状和其他异常的可能性。这些研究将包括脑切片中的电生理学记录、完整动物的生理和行为分析以及突触结构和功能的生化和形态学研究，使用最先进的化学遗传技术来操纵神经元和细胞的活动。通过确定 Mecp2 突变体中 mPFC 功能障碍的机制，希望这些研究能够促进针对 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患者。

项目成果

Activation of the Medial Prefrontal Cortex Reverses Cognitive and Respiratory Symptoms in a Mouse Model of Rett Syndrome.

内侧前额叶皮层的激活可逆转雷特综合征小鼠模型的认知和呼吸症状。

• 发表时间: 2017
• 影响因子: 3.4
• 作者: Howell, C James;Sceniak, Michael P;Lang, Min;Krakowiecki, Wenceslas;Abouelsoud, Fatimah E;Lad, Saloni U;Yu, Heping;Katz, David M
• 通讯作者: Katz, David M