REGULATION OF HIPPOCAMPAL CONNECTIVITY BY NEUROD2 MEDIATED TRANSCRIPTION

NEUROD2 介导的转录对海马连接的调节

• 批准号: 8361917
• 负责人: ANIRVAN GHOSH
• 金额: $ 3.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361917
• 关键词: Affect; Apical; BHLH Protein; Brain; Calcium; Characteristics; Dendrites; Development; Distal; Dyes; Fiber; Funding; Genetic Programming; Genetic Transcription; Grant; Head; Hippocampus (Brain); Image Analysis; Injection of therapeutic agent; Knockout Mice; Length; Link; Mediating; Morphology; National Center for Research Resources; Neurons; Pathway interactions; Presynaptic Terminals; Principal Investigator; Proteins; Regulation; Research; Research Infrastructure; Resources; Role; Signal Transduction; Source; Staining method; Stains; Structure; Synapses; United States National Institutes of Health; Vertebral column; activating transcription factor; calbindin; cost; density; hippocampal pyramidal neuron; lucifer yellow; mossy fiber; neural circuit; neurodevelopment; novel; relating to nervous system; synaptogenesis; transcription factor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The assembly of neural circuits in the developing brain is thought to require both genetically determined and activity-dependent mechanisms. Many of the long-term changes mediated by neural activity are dependent on calcium-activated transcription of new gene products. Thus, calcium-activated transcription factors provide a mechanism for linking extrinsic signals with genetic programs of neural development. NeuroD2 is a basic helix-loop-helix transcription factor previously isolated in our lab, using a screen for novel calcium-regulated transcription factors involved in cortical development. NeuroD2 expression is developmentally regulated in the hippocampus, peaking between P7 and P14, coincident with the primary period of synaptogenesis in this structure. Here, we demonstrate a role for NeuroD2 mediated transcription in the normal development of mossy fiber (MF) to CA3 connectivity. In NeuroD2 null mice, which have grossly normal brain structure, calbindin staining of the MF afferents revealed a dramatic and preferential reduction in the distal portion of the main MF bundle. Although the fiber tract extends the full length of the CA3 region, it fails to elaborate the characteristic enlargement known as the "end bulb" at its distal tip. TIMM staining for pre-synaptic terminals in the MF pathway revealed a similar, if not greater, reduction in synapse formation in this pathway. Analysis of post-synaptic morphology of CA3 pyramidal neurons by Lucifer Yellow dye injection revealed a similar reduction in the characteristic multi-headed spines of the proximal apical dendrites receiving MF input. Interestingly, the size and density of the more distally located classical spines was not affected in the KO. This raises the possibility that while NeuroD2 mediated transcription is required for the development of MF connectivity, synapses from other pathways onto the same neuron may form in a NeuroD2 independent manner. These studies begin to define a novel transcriptional pathway regulating the development of connectivity in a major excitatory component of hippocampal circuitry.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 人们认为，发育中的大脑中神经回路的组装被认为需要遗传确定和活动依赖性机制。神经活动介导的许多长期变化取决于新基因产物的钙激活转录。因此，钙激活的转录因子提供了将外在信号与神经发育的遗传程序联系起来的机制。 NeuroD2是先前在我们的实验室中分离出来的基本螺旋 - 环螺旋转录因子，它使用了与皮质发育有关的新型钙调节转录因子的屏幕。 NeuroD2表达在海马中受发展调节，在P7和P14之间达到峰值，与该结构中的一级突触发生时期相吻合。在这里，我们证明了NeuroD2介导的转录在苔藓纤维（MF）到CA3连接性的正常发育中的作用。在脑结构严重正常的NeuroD2 NULL小鼠中，MF传入的Calbindin染色显示出主MF束的远端部分急剧减少。尽管纤维道延长了CA3区域的全长，但它未能在其远端尖端详细说明被称为“末端灯泡”的特征性增大。 MF途径中突触前末端的TIMM染色显示，该途径中突触形成的降低相似，甚至更大。 Lucifer黄色染料注射对CA3锥体神经元的突触后形态的分析表明，近端顶端树突的特征性多头刺相似，接受了MF输入。有趣的是，在KO中，较远的经典刺的大小和密度不受影响。这提出了一种可能性，尽管神经2介导的转录需要发展MF连接性，但从其他途径到同一神经元的突触可能会以神经2的独立方式形成。这些研究开始定义一种新的转录途径，该途径调节海马电路主要兴奋分量中连通性的发展。