Rescue of GABAergic function in a mouse model of Rett syndrome

拯救 Rett 综合征小鼠模型中的 GABA 能功能

• 批准号: 8716355
• 负责人: Kerstin Maria Ure
• 金额: $ 5.51万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-13 至 2015-02-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8716355
• 关键词: Abnormal coordination; Accounting; Achievement; Aggressive behavior; Alleles; Animals; Antiepileptic Agents; Anxiety Disorders; Ataxia; Autistic Disorder; Behavior; Behavioral; Binding; Bipolar Disorder; Body Weight; Brain; Breathing; Cells; Cessation of life; Characteristics; Child; Chronic; Clinical Research; Code; Cognition; Cognitive deficits; DNA; Development; Disease; Electroencephalography; Electrophysiology (science); Employee Strikes; Encephalopathies; Engineering; Equilibrium; Eye; Female; Future; Gene Deletion; Genetic; Health; Heterozygote; Hypothalamic structure; Implant; Individual; Intervention; Knockout Mice; Language; Lead; Learning; Life; Light; Link; Manuals; Mediating; Memory impairment; Methyl-CpG-Binding Protein 2; Motor; Mus; Mutant Strains Mice; Mutation; Neonatal; Neurons; Obesity; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Pilot Projects; Play; Population; Pump; Rett Syndrome; Role; Schizophrenia; Seizures; Severities; Signal Transduction; Symptoms; Syndrome; Testing; Translating; Vigabatrin; X Inactivation; biological adaptation to stress; dopaminergic neuron; early onset; experience; feeding; gamma-Aminobutyric Acid; grasp; human male; improved; male; motor control; mouse model; nervous system disorder; neuropsychiatry; neurosteroids; public health relevance; receptor; research study; respiratory; skills

DESCRIPTION (provided by applicant): Rett syndrome (RTT) is a broad-ranging neurological disorder caused primarily by mutations in the X-linked methyl CpG-binding protein 2 (MECP2), a transcriptional regulator that binds methylated DNA. In females, the typical Rett syndrome appears following a period of apparently normal development and achievement of early milestones, only to lead to a rapid loss of acquired language and manual skills by the second year of life and the development of ataxia, respiratory dysrthythmias, seizures, and autistic features such as loss of eye contact. Mutations that would cause typical RTT in females produce a much more severe phenotype in human males (neonatal encephalopathy and death within the first years of life); milder mutations can lead to early- onset bipolar disorder or schizophrenia with motor abnormalities and obesity. Although the precise functions of MeCP2 protein continue to be debated, a number of mouse models have provided information about the origins of various phenotypes. Male Mecp2 nulls (most studies have used male mice to avoid the confounding influence of X chromosome inactivation on phenotypes), develop a severe RTT-like phenotype and die within the first four months of life. Most intriguing, however, have been studies examining the effect of deleting Mecp2 in specific neuronal groups: the Zoghbi lab discovered that loss of Mecp2 in GABAergic neurons captures the majority of RTT phenotypes-ataxia, stereotypies, breathing dysrhythmias, and learning and memory deficits. This result is all the more striking in light of the fact that GABAergic neurons account for only one-fifth of the brain's neuronal population, and loss of Mecp2 in these cells reduces GABA signaling by only ~30-40%. The Zoghbi lab proposed that partial reduction in GABA signaling mediates the phenotypes of these mice, possibly by perturbing the balance between excitatory and inhibitory signaling Alterations in this balance are suspected to underlie many other neuropsychiatric disorders, including schizophrenia, autism, obsessive-compulsive and anxiety disorders-all within the spectrum of phenotypes produced by MECP2 mutations. Given that Rett symptoms in the most severely compromised mice (male Mecp2 nulls) can be rescued by reactivation of Mecp2 in all neurons, I propose to test the hypothesis that rescue of Mecp2 deletion in GABAergic neurons is sufficient to reverse Rett-like symptoms in both male and female Mecp2 mutant mice by normalizing GABA signaling and improving excitatory/inhibitory balance. We recently conducted a pilot study in which we re-expressed Mecp2 in the GABAergic neurons of male Mecp2 null animals. We found significant rescue of body weight, ataxia, and grip strength (a readout of fine motor control). This suggests that the GABAergic circuitry not only plays a critical role in the pathogenesis of the disorder but is also a promising target for therapies for Rett syndrome patients. I propose to rescue GABA signaling by genetic and pharmacological means to lay the groundwork for future clinical studies.

描述（由申请人提供）：RETT综合征（RTT）是一种广泛的神经系统疾病，主要是由X连接的甲基CpG结合蛋白2（MECP2）突变引起的，这是一种结合甲基化DNA的转录调节剂。在女性中，典型的RETT综合征在一段时间正常发展和早期里程碑的成就之后出现，仅导致在生命的第二年和共济失调，呼吸疾病性疾病，癫痫发作，癫痫发作，癫痫发作和自闭症特征（例如眼神接触丧失）迅速丧失获得的语言和手动技能。在女性中会导致典型RTT的突变会在人类男性（新生儿脑病和死亡生命中的一年内）产生更严重的表型；温和的突变会导致早期发作双相情感障碍或精神分裂症患有运动异常和肥胖症。尽管MECP2蛋白的确切功能继续受到争论，但许多小鼠模型提供了有关各种表型起源的信息。雄性MECP2无效（大多数研究都使用雄性小鼠避免X染色体失活对表型的混杂影响），在生命的前四个月内发展出严重的RTT样表型并死亡。然而，最吸引人的是研究研究了特定神经元组中删除MECP2的效果的研究：Zoghbi实验室发现，GABA能神经元中MECP2的损失捕获了RTT表型 - ATAXIA-ATAXIA-刻板印象，刻板印象，呼吸障碍和学习障碍和学习记忆和学习和记忆力降低。鉴于GABA能神经元仅占大脑神经元种群的五分之一，而这些细胞中MECP2的损失仅占GABA信号的损失仅将GABA信号降低约30-40％。 Zoghbi实验室提出，GABA信号的部分减少介导了这些小鼠的表型，这可能是通过扰动这种平衡中兴奋性和抑制性信号改变之间的平衡，这是怀疑是许多其他神经精神疾病的基础，包括许多其他神经精神疾病，包括精神分裂，自动抗议和焦虑症，并在焦虑中 - 相对于焦虑症，广告素材 - 广告素材 - 广告素材，这些表现出现在现象中，这些疾病是广泛的，并且在这些神经精神疾病中广为人知。突变。 Given that Rett symptoms in the most severely compromised mice (male Mecp2 nulls) can be rescued by reactivation of Mecp2 in all neurons, I propose to test the hypothesis that rescue of Mecp2 deletion in GABAergic neurons is sufficient to reverse Rett-like symptoms in both male and female Mecp2 mutant mice by normalizing GABA signaling and improving excitatory/inhibitory 平衡。我们最近进行了一项试点研究，其中我们在雄性MECP2无效动物的GABA能神经元中重新表达了MECP2。我们发现了体重，共济失调和握力强度的大量挽救（对运动控制的读数）。这表明GABA能回路不仅在该疾病的发病机理中起着至关重要的作用，而且还是RETT综合征患者疗法的有希望的靶标。我建议通过遗传和药理学手段来挽救GABA信号传导，以为将来的临床研究奠定基础。