Neurexin-Neuroligin Trans-synaptic Interaction: Learning-related Synaptic Growth

Neurexin-Neuroligin 跨突触相互作用：学习相关的突触生长

• 批准号: 7395000
• 负责人: Yun-Beom Choi
• 金额: $ 16.79万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7395000
• 关键词: Afferent Neurons; Animals; Aplysia; Autistic Disorder; Biological; Cell Adhesion Molecules; Cell Nucleus; Cells; Chromosome Pairing; Coculture Techniques; Cytoplasmic Tail; Development; Disruption; Dominant-Negative Mutation; Functional disorder; Gene Expression; Gene Transfer Techniques; Genetic Complementation Test; Gills; Green Fluorescent Proteins; Growth; Image; Individual; Label; Learning; Life; Localized; Memory; Molecular; Molecular Cloning; Motor Neurons; Nervous system structure; Neurologic; Neurons; Neurotransmitters; Nuclear Translocation; Physiologic pulse; Physiological; Preparation; Protein Overexpression; Proteins; Pulse taking; Recovery of Function; Reflex action; Research Personnel; Role; Scaffolding Protein; Sensory; Serotonin; Signal Pathway; Signal Transduction; Synapses; Synaptic Vesicles; Synaptic plasticity; System; Techniques; Testing; Time; Training Activity; Varicosity; Withdrawal; developmental disease; experience; extracellular; immunocytochemistry; in vivo; long term memory; mutant; new growth; novel therapeutics; postnatal; postsynaptic; presynaptic; programs; reconstitution; repaired; skills; synaptogenesis

DESCRIPTION (provided by applicant): Studies in a variety of memory systems have suggested that the storage of long-term memory is associated with altered gene expression, the synthesis of new proteins, and the growth of new synaptic connections. However, little is known about molecular mechanisms that initiate and maintain the structural changes associated with long-term memory. A particularly useful system for delineating these molecular mechanisms is the gill-withdrawal reflex in Aplysia. Long-term sensitization of this reflex gives rise to robust increase in growth of new synaptic connections. Recently, initial attempts have been made in identifying some molecules important for do novo synaptic formation in the developing nervous system. Specifically, synaptic cell adhesion molecules, beta-neurexin (localized at the pre-synaptic neurons) and neuroligin (localized at the postsynaptic neurons), via trans-synaptic interaction with each other, have been found to be involved in synapse formation during development. These molecules may be also involved in the synaptic growth associated with the storage of long-term memory. CASK, a pre-synaptic scaffolding protein that interacts with beta-neurexin, can translocate to the nucleus and thereby regulates gene expression. Given the requirement of altered gene expression in the storage of long-term memory, CASK as a putative retrograde signal from the synapse to the nucleus triggered by beta-neurexin-neuroligin trans-synaptic interaction is an intriguing idea. The candidate will investigate the role of neuroligin, beta-neurexin, and CASK in the synaptic growth associated with the storage of long-term memory by exploiting the experimental accessibility of the Aplysia sensory-motor neuron co-culture preparation where the pre-synaptic structural changes associated with long-term synaptic plasticity are particularly robust and easy to study. Molecular cloning, gene transfer techniques using over-expression of synaptic marker proteins, time-lapse confocal imaging of individual, fluorescently-labeled pre-synaptic sensory neuron varicosities and physiological recording of the same sensory-motor neuron co-cultures will be used for the project. The training activities will enable the candidate to acquire the skills and experience necessary to become an independent neuroscientist equipped with the latest molecular and cellular biological techniques to investigate the learning-related synaptic growth and to develop novel therapeutic approaches to the sequel of synaptic dysfunction. Results from these studies should enhance understanding of a bidirectional signaling pathway from the synapse to the nucleus that regulates synaptic growth associated with the storage of long-term memory. In addition, it may provide some clues to the causes of postnatal developmental disorders such as autism that may be caused by disruption of synaptic plasticity and perhaps suggest novel therapeutic strategies for synaptic repair and remodeling leading recovery of function after various neurological insults.

描述（由申请人提供）：各种记忆系统中的研究表明，长期记忆的存储与基因表达的改变有关，新蛋白的合成以及新的突触连接的生长。但是，关于启动和维持与长期记忆相关的结构变化的分子机制知之甚少。描述这些分子机制的特别有用的系统是垂直垂直反射。这种反射的长期敏化会导致新突触连接的增长强大增加。最近，在确定发展神经系统中NOVO突触形成重要的一些分子方面进行了初步尝试。具体而言，突触细胞粘附分子，β-尿素（位于突触前神经元）和神经素（通过跨突触神经元位于突触后神经元中）通过跨突触的相互作用彼此相互作用，已被发现与彼此之间的跨突触相互作用有关。这些分子也可能参与与长期记忆的储存相关的突触生长。酒桶是一种与β-热毒素相互作用的突触前支架蛋白，可以转移到细胞核上，从而调节基因表达。鉴于需要改变基因表达在长期记忆中的储存中，cask作为从突触到β-纽雷克斯蛋白 - 蓝洛素跨突触相互作用触发的原子核的推定逆行信号是一个有趣的想法。候选人将通过利用Aplysia感觉运动神经元共培养的实验可及性，研究神经素，β-纽蛋白和桶的作用与长期记忆的储存相关的突触生长的作用与长期突触可塑性相关的变化特别强大且易于研究。分子克隆，使用突触标记蛋白过度表达的基因转移技术，单个，荧光标记的荧光型聚焦成像的延时共焦成像以及同一感觉运动神经元的生理记录以及相同的感觉神经元共培养的生理记录项目。培训活动将使候选人能够获得必要的技能和经验，以成为具有最新分子和细胞生物学技术的独立神经科学家，以研究与学习相关的突触增长，并开发出新的治疗方法，以换取突触功能障碍的续集。这些研究的结果应增强对从突触到调节与长期记忆储存相关的突触生长的核的双向信号通路的理解。此外，它可能为产后发育障碍（例如自闭症）的原因提供一些线索，这些原因可能是由于突触可塑性破坏而引起的，并且可能提出了各种神经系统损害后功能的突触修复和重塑领先恢复功能的新型治疗策略。