MECP2 Modulation of BDNF Signaling Shared Mechanism of Rett and Autism

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，由于其对个人（1：10，000 - 15，000全球出生），他们的家庭和社会的影响。RTT是由编码甲基CpG结合蛋白2（MeCP 2）的基因中的功能缺失突变引起的，MeCP 2是一种结合DNA启动子区域中甲基化CpG位点的转录调节因子。海马体中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Mecp 2的小鼠皮层神经元显示出由有利于突触抑制的兴奋/抑制失衡引起的低水平的神经元活性，并且Mecp 2表达水平调节海马神经元之间的兴奋性突触形成。脑源性神经营养因子（Brain-derived neurotrophic factor，Bdnf）是Mecp 2转录调控的靶基因之一，是一种活性依赖性突触发育、功能和可塑性的有效调节因子。考虑到BDNF对于抑制性GABA能突触的成熟至关重要，并且基于我们的初步结果，我们的一般假设是，由于Mecp 2缺陷神经元的活性依赖性BDNF释放减少而导致的抑制性GABA能突触发育受损导致海马中兴奋性和抑制性突触功能的不平衡。我们提出了以下四个具体目的：（1）检测神经元型Mecp 2基因敲除小鼠海马网络的过度兴奋是否是由CA 3区GABA能突触功能受损引起的;（2）检测神经元型Mecp 2基因敲除小鼠齿状回颗粒细胞轴突苔藓纤维释放的活性依赖性BDNF是否减少;（3）建立一种新的RTT模型-齿状颗粒细胞特异性Mecp 2敲除小鼠-并测试海马过度兴奋是否与颗粒细胞苔藓纤维的活动依赖性BDNF释放受损相关;（4）测试增强BDNF表达或模拟BDNF/TrkB信号传导是否防止Mecp 2缺失小鼠和齿状颗粒细胞特异性Mecp 2敲除小鼠中的海马过度兴奋。我们预计，所提出的实验将产生新的信息的后果Mecp 2删除的兴奋/抑制海马体中的平衡，揭示基本的大脑机制参与RTT和自闭症谱系障碍的神经病理学，并测试实验的基本原理，以减轻认知障碍和精神发育迟滞的儿童与相关的神经发育障碍。

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.