MeCP2 Modulation of BDNF Signaling: Shared Mechanisms of Rett and Autism

MeCP2 调节 BDNF 信号：Rett 和自闭症的共同机制

• 批准号: 8018589
• 负责人: Lucas D Pozzo-Miller
• 金额: $ 31.41万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018589
• 关键词: Affect; Area; Autistic Disorder; Axon; Binding; Biological Assay; Birth; Brain; Brain-Derived Neurotrophic Factor; Child; Childhood; DNA; DNA-Binding Proteins; Development; Disease; Dyes; Equilibrium; Excitatory Postsynaptic Potentials; Excitatory Synapse; Exons; Family; Gene Targeting; Genes; Genetic Recombination; Hippocampus (Brain); Image; Impaired cognition; Individual; Inhibitory Synapse; Insulin-Like Growth Factor I; Interneurons; Knockout Mice; Link; Mediating; Membrane; Mental Retardation; Methyl-CpG-Binding Protein 2; Modeling; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Pathway interactions; Phenotype; Promoter Regions; Rett Syndrome; Signal Transduction; Site; Slice; Societies; Synapses; System; Testing; Therapeutic; Transcriptional Regulation; Transgenes; Whole-Cell Recordings; autism spectrum disorder; base; dentate gyrus; granule cell; hippocampal pyramidal neuron; loss of function mutation; mossy fiber; neuropathology; novel; postnatal; presynaptic; prevent; public health relevance; receptor; research study; synaptic function; synaptic inhibition; synaptogenesis; voltage

DESCRIPTION (provided by applicant): Rett syndrome (RTT), an autism spectrum disorder, is a devastating childhood disorder due to its impact on individuals (1:10,000-15,000 births worldwide), their families and society. RTT is caused by loss-of- function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2), a transcriptional regulator that binds to methylated CpG sites in promoter regions of DNA. An imbalance of excitatory and inhibitory synaptic function in the hippocampus has been implicated in neurodevelopmental disorders associated with cognitive impairments and mental retardation. Mouse cortical neurons lacking Mecp2 show low levels of neuronal activity caused by an excitation/inhibition imbalance that favors synaptic inhibition, and Mecp2 expression levels modulate excitatory synapse formation between hippocampal neurons. One of the target genes of Mecp2 transcriptional control is Brain-derived neurotrophic factor (Bdnf), a potent modulator of activity-dependent synaptic development, function and plasticity. Considering that BDNF is critical for the maturation of inhibitory GABAergic synapses, and based on our Preliminary Results, our general hypothesis is that impaired development of inhibitory GABAergic synapses due to reduced activity- dependent BDNF release from Mecp2-deficient neurons causes an imbalance of excitatory and inhibitory synaptic function in the hippocampus. We propose the following four Specific Aims: (1) test if the hyperexcitable hippocampal network of neuronal Mecp2 null mice is caused by impaired GABAergic synapse function in area CA3; (2) test whether activity-dependent BDNF release from mossy fibers, the axons of dentate gyrus granule cells, is reduced in neuronal Mecp2 null mice; (3) generate a novel RTT model - dentate granule cell-specific Mecp2 knockout mice - and test whether hippocampal hyperexcitability is associated with impaired activity-dependent BDNF release from granule cell mossy fibers; (4) test if enhancing BDNF expression or mimicking BDNF/TrkB signaling prevents hippocampal hyperexcitability in Mecp2 null mice and dentate granule cell-specific Mecp2 knockout mice. We anticipate that the proposed experiments will yield novel information regarding the consequences of Mecp2 deletion for the excitation/inhibition balance in the hippocampus, uncovering fundamental brain mechanisms involved in the neuropathology of RTT and Autism Spectrum Disorders, and testing an experimental rationale to relieve cognitive impairments and mental retardation in children with associated neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder associated with autism and mental retardation, which is caused by mutations in MECP2, a DNA-binding protein that regulates target genes, including Bdnf. We will test whether impaired development of hippocampal inhibitory synapses due to reduced BDNF release contributes to the excitatory/inhibitory imbalance of synaptic function implicated in cognitive impairments and autism in RTT.

描述（由申请人提供）：自闭症谱系障碍Rett综合征（RTT）是一种毁灭性的儿童疾病，因为它对个人的影响（全球1：10,000-15,000个出生），其家庭和社会。 RTT是由编码甲基-CPG结合蛋白2（MECP2）的基因中的功能丧失引起的，这是一种转录调节剂，与DNA启动子区域中甲基化的CpG位点结合。海马中兴奋性和抑制性突触功能的失衡与认知障碍和智力低下有关的神经发育障碍涉及。缺乏MECP2的小鼠皮质神经元显示出较低的神经元活性，这是由于激发/抑制不平衡而引起的，促进突触抑制，而MECP2表达水平调节海马神经元之间的兴奋性突触形成。 MECP2转录控制的目标基因之一是脑衍生的神经营养因子（BDNF），这是活性依赖性突触发育，功能和可塑性的有效调节剂。 Considering that BDNF is critical for the maturation of inhibitory GABAergic synapses, and based on our Preliminary Results, our general hypothesis is that impaired development of inhibitory GABAergic synapses due to reduced activity- dependent BDNF release from Mecp2-deficient neurons causes an imbalance of excitatory and inhibitory synaptic function in the hippocampus.我们提出以下四个特定目的：（1）测试神经元MECP2 NULL小鼠的过度外海马网络是由CA3面积的Gabaergic Synapse功能受损引起的； （2）在神经元MECP2无效小鼠中降低了从苔藓纤维（齿状回和颗粒细胞的轴突）中释放活性依赖性的BDNF； （3）生成一种新型的RTT模型 - 牙齿颗粒细胞特异性MECP2敲除小鼠 - 并测试海马过度X型是否与活性依赖性BDNF从颗粒细胞苔藓纤维释放中释放受损有关； （4）测试是否增强了BDNF表达或模仿BDNF/TRKB信号传导可防止MECP2无效小鼠和牙齿颗粒细胞特异性MECP2敲除小鼠的海马过度刺激性。我们预计提出的实验将产生有关MECP2缺失对海马的激发/抑制平衡的后果的新信息，发现RTT神经病理和自闭症谱系障碍神经病理学涉及的基本大脑机制以及与识别性障碍相关的实验性障碍和精神上的习惯，并测试了与精神障碍。 公共卫生相关性：RETT综合征（RTT）是一种与自闭症和智力低下有关的X连锁神经发育障碍，这是由MECP2突变引起的，MECP2是一种调节靶基因的DNA结合蛋白，包括BDNF。我们将测试由于BDNF释放减少而导致海马抑制突触的发展是否有助于与RTT中认知障碍和自闭症有关的突触功能的兴奋/抑制失衡。