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: 7928666
• 负责人: Lucas D Pozzo-Miller
• 金额: $ 32.05万
• 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/7928666
• 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 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）：Rett综合征（RTT）是一种自闭症谱系障碍，是一种毁灭性的儿童疾病，它对个人（全球1:10 000- 1.5万新生儿）、他们的家庭和社会都有影响。RTT是由编码甲基CpG结合蛋白2 （MeCP2）基因的功能缺失突变引起的，MeCP2是一种结合DNA启动子区域甲基化CpG位点的转录调节因子。海马兴奋性和抑制性突触功能的不平衡与认知障碍和智力迟钝相关的神经发育障碍有关。缺乏Mecp2的小鼠皮质神经元表现出低水平的神经元活动，这是由于兴奋/抑制失衡导致的，有利于突触抑制，Mecp2表达水平调节海马神经元之间兴奋性突触的形成。Mecp2转录调控的靶基因之一是脑源性神经营养因子（Bdnf），它是活动依赖性突触发育、功能和可塑性的有效调节剂。考虑到BDNF对抑制性gabaergy突触的成熟至关重要，基于我们的初步结果，我们的一般假设是，由于mecp2缺陷神经元活性依赖性BDNF释放减少，抑制性gabaergy突触发育受损，导致海马兴奋性和抑制性突触功能失衡。我们提出以下四个具体目的：(1)检测神经元Mecp2缺失小鼠的海马体网络过度兴奋是否由CA3区gaba能突触功能受损引起；(2)检测Mecp2缺失小鼠齿状回颗粒细胞轴突苔藓纤维中活动依赖性BDNF的释放是否减少；(3)建立一种新的RTT模型-齿状颗粒细胞特异性Mecp2敲除小鼠-并测试海马的高兴奋性是否与颗粒细胞苔藓纤维中活动依赖性BDNF释放受损有关；(4)检测增强BDNF表达或模拟BDNF/TrkB信号传导是否能阻止Mecp2缺失小鼠和齿状颗粒细胞特异性Mecp2敲除小鼠的海马高兴奋性。我们期望我们提出的实验将提供关于Mecp2缺失对海马兴奋/抑制平衡影响的新信息，揭示RTT和自闭症谱系障碍的神经病理学相关的基本脑机制，并为缓解相关神经发育障碍儿童的认知障碍和智力迟钝提供实验依据。