Circuit-based therapy for rett syndrome

雷特综合征的基于电路的治疗

• 批准号: 7860412
• 负责人: Michela Fagiolini
• 金额: $ 21.47万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860412
• 关键词: ARHGEF5 gene; Accounting; Acetylation; Acute; Address; Adult; Affect; Agonist; Animal Experiments; Animal Model; Animals; Autistic Disorder; Behavioral; Benzodiazepines; Biological Assay; Biological Models; Boston; Brain; Brain-Derived Neurotrophic Factor; Breeding; Carbolines; Complex; Contrast Sensitivity; DNA; Data; Defect; Dependence; Development; Disease; Epigenetic Process; Equilibrium; Etiology; Event; Evoked Potentials; Exhibits; Eye; Female; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genotype; Grant; Health; Histone Acetylation; Histone H3; Immunohistochemistry; Impairment; Implant; Individual; Infusion procedures; Knock-in Mouse; Knockout Mice; Knowledge; Laboratories; Life; Link; Methyl-CpG-Binding Protein 2; Modification; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Mutate; Mutation; Neurodevelopmental Disorder; Neurologic; Neurons; Ocular Dominance; Pathogenesis; Pathway interactions; Pattern; Pediatric Hospitals; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Phosphorylation; Point Mutation; Process; Property; Recovery; Regulation; Repression; Research; Resolution; Rett Syndrome; Role; Scheme; Sensory; Shapes; Solutions; Staging; Symptoms; Synapses; Syndrome; System; Techniques; Testing; Therapeutic; Time; Translations; Vertebral column; Vision; Visual; Visual Acuity; Visual Cortex; area striata; base; chromatin modification; critical period; dark rearing; demethylation; early childhood; early onset; experience; gene function; gene repression; in vivo; infancy; male; methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; monocular deprivation; mouse model; mutant; orientation selectivity; overexpression; postnatal; prevent; public health relevance; receptive field; research study; restoration; success; therapeutic target; transmission process

DESCRIPTION (provided by applicant): The first symptoms of neurodevelopmental disorder such as Rett Syndrome appear during early childhood when sensory experience is sculpting neuronal circuits in what it will become the mature brain6. Mutations in MeCP2 gene account for 80% of RTT cases. MeCP2 regulates the expression of a wide range of genes and can coordinate either transcriptional repression or activation depending on the molecular and/or cellular context. This directly implicates an epigenetic pathway in neurodevelopmental disorders. Interestingly, perturbation of MeCP2 expression shifts the dynamic cortical excitatory/inhibitory balance in favor of inhibition in visual cortex18. Moreover, sensory experience can selectively induce MeCP2 phosphorylation, regulating dendritic patterning, spine morphogenesis, and BDNF transcription101. Surprisingly, RTT-like neurological defects can be rescued by delayed restoration of MeCP2 gene31,32,54 as well as overexpression of BDNF9. By establishing the principle of reversibility in mice, these studies suggest that RTT and related disorders are also reversible, even in the late stages of the disease. Our research has revealed that excitatory/inhibitory balance dictates the timing of critical periods of visual cortical maturation23. Direct manipulation of this balance can accelerate or delayed activity-dependent processes and can be used successfully to rescue plasticity defects23-25,46,47 . Perturbing neuronal activity causes aberrant gene-expression patterns, many of which are linked to misregulated epigenetic systems. Our central hypothesis is that the excitatory/inhibitory balance drives MeCP2 regulation of gene translation and repression in an activity-dependent manner during critical periods of heightened cortical plasticity in infancy. Their disruption leads to the complex behavioral phenotype of neurodevelopmental disorders such as Rett Syndrome. Hence, manipulation of Excitatory/Inhibitory balance will be used to rescue cortical impairments in animal models of Rett syndrome. By applying in vivo electrophysiological techniques, we aim to reveal role of MeCP2 function in excitatory/inhibitory circuit balance during cortical circuit refinement. The results will provide potential therapeutic strategies for reactivating brain plasticity in neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: In the present grant, we propose to test the hypothesis that an excitatory/inhibitory balance drives a complex epigenetic state of gene translation and repression in an activity-dependent manner during critical periods of heightened cortical plasticity in infancy. Their disruption leads to the complex behavioral phenotype of neurodevelopmental disorders such as Rett Syndrome and ASDs. By applying in vivo electrophysiological techniques, we aim to reveal MeCP2 function in relation to excitatory/inhibitory circuit balance in cortical circuit refinement. The results will provide potential therapeutic strategies for reactivating brain plasticity in animal models of Rett Syndrome.

描述（由申请人提供）：雷特综合症等神经发育障碍的最初症状出现在儿童早期，当时感觉经验正在塑造神经元回路，并将成为成熟的大脑6。 MeCP2 基因突变占 RTT 病例的 80%。 MeCP2 调节多种基因的表达，并可以根据分子和/或细胞背景协调转录抑制或激活。这直接暗示了神经发育障碍中的表观遗传途径。有趣的是，MeCP2 表达的扰动会改变动态皮层兴奋/抑制平衡，有利于视觉皮层的抑制18。此外，感觉体验可以选择性诱导 MeCP2 磷酸化，调节树突模式、脊柱形态发生和 BDNF 转录101。令人惊讶的是，RTT 样神经缺陷可以通过 MeCP2 基因的延迟恢复31,32,54 以及 BDNF9 的过度表达来挽救。通过在小鼠中建立可逆性原理，这些研究表明 RTT 和相关疾病也是可逆的，即使在疾病的晚期也是如此。我们的研究表明，兴奋/抑制平衡决定了视觉皮层成熟关键时期的时间安排23。直接操纵这种平衡可以加速或延迟活动依赖性过程，并可成功用于挽救可塑性缺陷23-25,46,47。扰乱神经元活动会导致异常的基因表达模式，其中许多与失调的表观遗传系统有关。我们的中心假设是，在婴儿期皮质可塑性增强的关键时期，兴奋/抑制平衡以活动依赖性方式驱动 MeCP2 对基因翻译和抑制的调节。它们的破坏导致神经发育障碍（例如雷特综合症）的复杂行为表型。因此，兴奋/抑制平衡的操纵将用于挽救雷特综合征动物模型的皮质损伤。通过应用体内电生理学技术，我们的目标是揭示 MeCP2 功能在皮质回路细化过程中兴奋/抑制回路平衡中的作用。研究结果将为重新激活神经发育障碍中的大脑可塑性提供潜在的治疗策略。公共健康相关性：在目前的资助中，我们建议检验这样的假设：在婴儿期皮质可塑性增强的关键时期，兴奋/抑制平衡以活动依赖的方式驱动基因翻译和抑制的复杂表观遗传状态。它们的破坏导致神经发育障碍（例如雷特综合症和自闭症谱系障碍）的复杂行为表型。通过应用体内电生理学技术，我们的目标是揭示 MeCP2 与皮层回路细化中兴奋/抑制回路平衡相关的功能。研究结果将为重新激活雷特综合征动物模型中的大脑可塑性提供潜在的治疗策略。