Mechanisms of Central Neuron Synaptogenesis

中枢神经元突触发生的机制

基本信息

批准号：
8389529
负责人：
ANN M CRAIG
金额：
$ 24.13万
依托单位：
UNIVERSITY OF BRITISH COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8389529
关键词：
Alzheimer&apos s Disease Amyloid beta-Protein Precursor Animal Model Antibodies Autistic Disorder Axon Behavior Behavioral Behavioral Assay Binding Biochemical Biochemistry Biological Assay Brain Brain region COS Cells Cadherins Caenorhabditis elegans Calcium-Binding Domain Cell Fractionation Cell physiology Chemicals Cleaved cell Coculture Techniques Cognition Cognition Disorders Cognitive Collaborations Communication Complementary DNA Complex Confocal Microscopy Data Defect Development Disease Electron Microscopy Electrophysiology (science)Epilepsy Epitopes Family Family Study Future Gene Family Genes Glutamates Goals Grant Health Hippocampus (Brain)Homologous Gene Hour Human Individual Injury Integral Membrane Protein Knock-out Knockout Mice Lead Learning Length Link Lower Organism Mental Retardation Mental disorders Modeling Molecular Molecular Genetics Morphology Mus Mutation Natural regeneration Neurodegenerative Disorders Neurons Neurotransmitters Parkinson Disease Pattern Peptide Hydrolases Pharmaceutical Preparations Physiological Physiology Process Property Protease Inhibitor Proteins Proteolysis Recruitment Activity Regulation Reporting Research Role Schizophrenia Series Signal Transduction Site Stroke Structure Surface Susceptibility Gene Synapses Synaptic Transmission Synaptic plasticity Tertiary Protein Structure Variant Western Blotting autism spectrum disorder base brain cell brain morphology classical conditioning cognitive function design extracellular fluorescence imaging gamma-Aminobutyric Acid gene function improved in vivo injured memory process memory recall morris water maze nervous system disorder novel object recognition overexpression postsynaptic presynaptic protein function repaired research study synaptic function synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Brain development requires orchestrated formation of connections between nerve cells. These synaptic connections are the main units of communication in the brain, where chemical neurotransmitter signaling occurs. This proposal is on synaptic organizing proteins, genes that function as master regulators of synaptic development. Such proteins alone can trigger formation of nerve cell connections. In preliminary studies, from an unbiased screen we identified a new protein that triggers development of presynaptic connections in contacting nerve cell processes. It is one of a family of 3 highly related proteins. The proposed experiments will assess the ability of these 3 synaptic organizing proteins to drive formation of nerve cell connections of different neurotransmitter types, and will identify protein domains responsible. These novel synaptic organizing proteins can be cleared by extracellular proteolysis. Preliminary data suggests that cleavage abolishes synaptic organizing activity; thus we will study how cleavage is regulated. Finally, a major aim is to use a combination of mouse molecular genetics, fluorescence imaging, biochemistry, electrophysiology, and behavioral assays to determine the importance of these genes in brain development and synaptic function. This combined in vivo approach will allow an understanding of how these genes contribute to brain wiring, synaptic composition, structure, and function, and how changes in specific synapses result in behavioral changes. Such approaches often result in useful models for psychiatric disorders. The central hypothesis is that these genes are crucial for organizing synaptic development, for recruiting molecular components essential for proper synaptic structure and function in brain circuits important for cognition. Variation in one of these genes is linked to word recall ability, and lower organisms lacking the single homologous gene are deficient in learning. Furthermore, variants in the major synaptic organizing gene families studied to date, neuroligins and neurexins, predispose to autism spectrum disorders, schizophrenia, and mental retardation. Thus, in studying these synaptic organizing genes, we hope to increase our understanding of the molecular basis for cognitive disorders and to help design rational drug treatments. As triggers for building synaptic connections, these genes may also have implications for a number of neurological disorders from epilepsy and stroke to Alzheimer's and Parkinson's diseases. It may be possible to harness the ability of these genes to trigger formation of nerve cell connections to repair and regenerate the lost and injured connections in these debilitating disorders.

描述（由申请人提供）：大脑发育需要神经细胞之间的连接的编排。这些突触连接是化学神经递质信号传导的主要通信的主要单位。该建议是关于突触组织蛋白，该蛋白质是突触发育的主要调节剂的基因。单独的蛋白质可以触发神经细胞连接的形成。在初步研究中，从公正的屏幕中，我们确定了一种新蛋白质，该蛋白会触发与神经细胞过程中突触前连接的发展。它是3个高度相关蛋白质的家族之一。提出的实验将评估这3种突触组织蛋白驱动不同神经递质类型的神经细胞连接形成的能力，并将确定负责的蛋白质结构域。这些新型突触组织蛋白可以通过细胞外蛋白水解清除。初步数据表明，乳沟消除了突触组织活动。因此，我们将研究如何调节切割。最后，一个主要目的是将小鼠分子遗传学，荧光成像，生物化学，电生理学和行为测定的组合确定这些基因在脑发育和突触功能中的重要性。这种结合的体内方法将使这些基因如何促进大脑接线，突触组成，结构和功能，以及特定突触的变化如何导致行为变化。这种方法通常会导致精神疾病的有用模型。中心假设是这些基因对于组织突触发育至关重要，对于募集适当的突触结构和功能对认知重要的脑电路的功能所必需的分子成分至关重要。这些基因之一的变化与单词回忆能力有关，缺乏单一同源基因的较低生物缺乏学习。此外，迄今为止研究的主要突触组织基因家族的变体，神经素和神经毒素，倾向于自闭症谱系障碍，精神分裂症和精神降低。因此，在研究这些突触组织基因时，我们希望增加对认知障碍分子基础的理解，并帮助设计合理的药物治疗。作为建立突触连接的触发因素，这些基因也可能对从癫痫和中风到阿尔茨海默氏症和帕金森氏病的许多神经系统疾病产生影响。可以利用这些基因触发神经细胞连接形成的能力来修复和再生这些令人衰弱的疾病中丢失和受伤的连接。